JP2009502886A - Macrocyclic inhibitor of hepatitis C virus - Google Patents

Abstract

各点線が場合による二重結合を示し；ＸがＮ、ＣＨであり、そしてＸが二重結合を含む場合、それはＣであり；Ｒ^１が−ＯＲ^６、−ＮＨ−ＳＯ_２Ｒ^７であり；Ｒ^２が水素であり、そしてＸがＣ又はＣＨである場合、Ｒ^２はＣ_１−６アルキルであることもでき；Ｒ^３が水素、Ｃ_１−６アルキル、Ｃ_１−６アルコキシＣ_１−６アルキル又はＣ_３−７シクロアルキルであり；ｎが３、４、５又は６であり；Ｒ^４及びＲ^５が、それらが結合する窒素原子と一緒になって、式（ＩＩ）から選ばれる二環式環系を形成し、ここで該環系は場合により１〜３個の置換基で置換されていることができ；Ｒ^６が水素；アリール；Ｈｅｔ；場合によりＣ_１−６アルキルで置換されていることができるＣ_３−７シクロアルキル；あるいは場合によりＣ_３−７シクロアルキル、アリール又はＨｅｔで置換されていることができるＣ_１−６アルキルであり；Ｒ^７がアリール；Ｈｅｔ；場合によりＣ_１−６アルキルで置換されていることができるＣ_３−７シクロアルキル；あるいは場合によりＣ_３−７シクロアルキル、アリール又はＨｅｔで置換されていることができるＣ_１−６アルキルであり；アリールがフェニル又はナフチルであり、それらのそれぞれは場合により１〜３個の置換基で置換されていることができ；Ｈｅｔが、それぞれＮ、Ｏ又はＳから独立して選ばれる１〜４個のヘテロ原子を含有し、場合により１〜３個の置換基で置換されていることができる５もしくは６員飽和、部分的不飽和もしくは完全に不飽和の複素環式環である式（Ｉ）のＨＣＶ複製の阻害剤及びそのＮ−オキシド、塩又は立体異性体、化合物（Ｉ）を含有する製薬学的組成物ならびに化合物（Ｉ）の製造方法。式（Ｉ）のＨＣＶの阻害剤とリトナビルとの生物利用性組み合わせも提供される。[Chemical 1]

Each dotted line represents an optional double bond; when X is N, CH, and X contains a double bond, it is C; R ¹ is —OR ⁶ , —NH—SO ₂ R ⁷ When R ² is hydrogen and X is C or CH, R ² can also be C _1-6 alkyl; R ³ is hydrogen, C _1-6 alkyl, C _1-6 alkoxy C _{1 -6} alkyl or C _3-7 cycloalkyl; n is 3, 4, 5 or 6; R ⁴ and R ⁵ together with the nitrogen atom to which they are attached are selected from formula (II) Wherein the ring system can be optionally substituted with 1 to 3 substituents; R ⁶ is hydrogen; aryl; Het; optionally C _1-6 alkyl C or by the case; C _3-7 cycloalkyl in which may optionally be substituted _{C 3-7} which may be substituted by _{C 1-6} alkyl optionally; _-7 cycloalkyl, _{C 1-6} is alkyl which may be substituted with aryl or Het; ^{R 7} is aryl; Het Cycloalkyl; or C _1-6 alkyl optionally substituted with C _3-7 cycloalkyl, aryl or Het; aryl is phenyl or naphthyl, each of which is optionally 1-3 Het contains 1 to 4 heteroatoms independently selected from N, O or S and is optionally substituted with 1 to 3 substituents Inhibitors of HCV replication of formula (I) which are 5- or 6-membered saturated, partially unsaturated or fully unsaturated heterocyclic rings which can be A pharmaceutical composition containing a side, a salt or a stereoisomer, compound (I), and a method for producing compound (I). A bioavailability combination of an inhibitor of HCV of formula (I) and ritonavir is also provided.

Description

  The present invention relates to a macrocyclic compound having inhibitory activity on replication of hepatitis C virus (HCV). The invention further relates to compositions comprising these compounds as active ingredients and methods for preparing these compounds and compositions.

  Hepatitis C virus is the leading cause of chronic liver disease worldwide and has been the focus of significant medical research. HCV is a member of the Flaviviridae family of viruses belonging to the genus hepacivirus and is part of the flavivirus family, including dengue virus, yellow fever virus, and bovine virus. It is closely related to the family of animal pestiviruses, including viral diarrhea virus (BVDV). HCV is a positive-sense single-stranded RNA virus having a genome of about 9,600 bases. The genome includes a central reading frame that encodes both the 5 ′ and 3 ′ untranslated regions of RNA secondary structure and a polyprotein of about 3,010 to 3,030 amino acids. Become. The polyprotein encodes 10 gene products, which are precursors by an orchestrated series of co-translational and post-translational endoproteolytic cleavage mediated by both host and viral proteases. From body polyproteins. Viral structural proteins include the core nucleocapsid protein and two envelope glycoproteins E1 and E2. Non-structural (NS) proteins encode several essential viral enzyme functions (helicase, polymerase, protease) as well as proteins of unknown function. Viral genome replication is mediated by an RNA-dependent RNA polymerase encoded by non-structural protein 5b (NS5B). In addition to the polymerase, both viral helicase and protease functions encoded in the bifunctional NS3 protein have been shown to be essential for HCV RNA replication. In addition to the NS3 serine protease, HCV also encodes a metalloproteinase in the NS2 region.

  Following the initial acute infection, the majority of infected patients develop chronic hepatitis because HCV replicates preferentially in hepatocytes but is not directly cytotoxic. In particular, the lack of a vigorous T-lymphocyte reaction and the high tendency of the virus to mutate appears to facilitate a high rate of chronic infection. Chronic hepatitis progresses to liver fibrosis and can lead to cirrhosis, end-stage liver disease and HCC (hepatocellular carcinoma), which is the primary cause of liver transplantation.

  There are 6 major HCV genotypes and more than 50 subtypes, which are distributed geographically in different ways. Type 1 HCV is the dominant genotype in Europe and the United States. The extensive genetic heterogeneity of HCV has important diagnostic and clinical implications, possibly explaining difficulties in vaccine development and lack of response to therapy.

  Transmission of HCV can occur through contact with contaminated blood or blood products following, for example, blood transfusion or intravenous drug use. The introduction of diagnostic tests used in blood screening has led to a tendency to reduce the incidence of transfusion-post HCV. However, given the slow progression to end-stage liver disease, existing infections will continue to provide significant medical and economic burden for decades.

Current HCV treatment is based on interferon-alpha (IFN-α) combined with ribavirin (polyethylene glycol derivatized). This combination therapy produces a sustained virological response in more than 40% of patients infected with genotype 1 virus and in about 80% of patients infected with genotypes 2 and 3. In addition to its limited effectiveness on type 1 HCV, this combination therapy has significant side effects and is not well tolerated in many patients. Major side effects include influenza-like symptoms, hematological abnormalities and neuropsychiatric symptoms. Therefore, there is a need for a more effective, simple and more tolerable treatment.

Recently, two peptidomimetic HCV protease inhibitors, namely BILN-2061 disclosed in Patent Document 1 and VX-950 disclosed in Patent Document 2, have received attention as clinical candidate drugs. Several similar HCV protease inhibitors have also been disclosed in the academic and patent literature. HCV mutants in which continuous administration of BILN-2061 or VX-950 is resistant to the respective drug, so-called drug escape mutants (drug
The choice of escape mutants has already been made clear. These drug escape mutants have characteristic mutations in the HCV protease genome, notably D168V, D168A and / or A156S. Therefore, additional drugs with different resistance patterns are needed to give treatment options to failing patients, and combination therapy with multiple drugs, even for first line treatment The future is likely to be normal.

Experience with HIV drugs and especially HIV protease inhibitors has further emphasized that sub-optimal pharmacokinetics and complex medication management quickly results in inadvertent compliance failure. This in turn means that the 24-hour trough concentration (minimum plasma concentration) for each drug in HIV management frequently falls below the IC ₉₀ or ED ₉₀ threshold over a large portion of the day. A 24-hour trough level of at least IC ₅₀ and more realistically IC ₉₀ or ED ₉₀ appears to be essential to delay the appearance of drug escape mutants.

  Achieving the pharmacokinetics and drug metabolism necessary to enable such trough levels presents severe challenges to drug design. The strong peptidomimetic nature of prior art HCV protease inhibitors with multiple peptide bonds represents a pharmacokinetic hurdle to effective dosage management.

  There is a need for HCV inhibitors that can overcome the shortcomings of current HCV treatments, such as side effects, limited efficacy, emergence of tolerance and failure to comply.

  Patent Document 3 relates to macrocyclic carboxylic acids and acylsulfonamides as HCV replication inhibitors and pharmaceutical compositions, methods for treating hepatitis C virus infection, and methods for treating liver fibrosis.

International Publication No. 00/59929 Pamphlet International Publication No. 03/87092 Pamphlet International Publication No. 05/037214 Pamphlet

  The present invention relates to the following related pharmacological properties: titer, reduced cytotoxicity, improved pharmacokinetics, improved resistance profile, acceptable dosage and drug burden. HCV inhibitors that are superior in one or more of the above.

Furthermore, the compounds of the present invention have a relatively low molecular weight and are readily synthesized starting from starting materials that are commercially available or can be readily obtained via synthetic methods known in the art. is there.

  The present invention relates to inhibitors of HCV replication, which have the formula (I):

[Where:
Each dotted line (indicated by -----) indicates an optional double bond;
X is N, CH, and if X contains a double bond, it is C;
R ¹ is —OR ⁶ , —NH—SO ₂ R ⁷ ;
R ² is hydrogen, and when X is C or CH, R ² can also be C _1-6 alkyl;
R ³ is hydrogen, C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl or C _3-7 cycloalkyl;
n is 3, 4, 5 or 6;
R ⁴ and R ⁵ together with the nitrogen atom to which they are attached

Forming a bicyclic ring system selected from: wherein the ring system is optionally halo, hydroxy, oxo, nitro, cyano, carboxyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkoxy C Substituted with 1, 2 or 3 substituents independently selected from _1-6 alkyl, C _1-6 alkylcarbonyl, C _1-6 alkoxycarbonyl, amino, azide, mercapto, polyhaloC _1-6 alkyl Can be;
R ⁶ is hydrogen; aryl; Het; C _3-7 cycloalkyl optionally substituted with C _1-6 alkyl; or optionally substituted with C _3-7 cycloalkyl, aryl or Het C _1-6 alkyl which can be
R ⁷ is aryl; Het; C _3-7 cycloalkyl optionally substituted with C _1-6 alkyl; or optionally C _3-7 cycloalkyl, aryl or He
C _1-6 alkyl, which can be substituted with t;
Aryl as a group or part of a group is phenyl or naphthyl, each of which is optionally halo, hydroxy, nitro, cyano, carboxyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkoxyC _1-6 alkyl, C _1-6 alkylcarbonyl, amino, mono- or diC _1-6 alkylamino, azide, mercapto, polyhaloC _1-6 alkyl, polyhaloC _1-6 alkoxy, C _3-7 cycloalkyl, Can be substituted with 1, 2 or 3 substituents selected from pyrrolidinyl, piperidinyl, piperazinyl, 4-C _1-6 alkyl-piperazinyl, 4-C _1-6 alkylcarbonyl-piperazinyl and morpholinyl; in morpholinyl and piperidinyl groups may optionally one or two C _1- It can be substituted with an alkyl group;
Het as a group or part of a group is a 5 or 6 membered saturated, partially unsaturated or fully unsaturated containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, respectively A heterocyclic ring and optionally halo, hydroxy, nitro, cyano, carboxyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkylcarbonyl, respectively , Amino, mono- or diC _1-6 alkylamino, azide, mercapto, polyhaloC _1-6 alkyl, polyhaloC _1-6 alkoxy, C _3-7 cycloalkyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-C _{1- 6} alkyl - piperazinyl, _{4-C 1-6} alkylcarbonyl - independently from the group consisting of piperazinyl and morpholinyl That Te is substituted with 1, 2 or 3 substituents selected can be; wherein morpholinyl and piperidinyl groups may be substituted with one or two C _1-6 alkyl groups optionally]
As well as its N-oxides, salts and stereoisomers.

  The present invention further provides a process for the preparation of compounds of formula (I), their N-oxides, addition salts, quaternary amines, metal complexes and stereochemical isomers, their intermediates and compounds of formula (I) The use of intermediates in

  The present invention relates to the compound of formula (I) itself, its N-oxide, addition salts, quaternary amines, metal complexes and stereochemical isomers for use as a medicament. The invention further relates to a pharmaceutical composition comprising a compound as described above for administration to a patient suffering from HCV infection. The pharmaceutical composition can comprise a combination of the aforementioned compounds and other anti-HCV drugs.

  The invention also relates to the use of a compound of formula (I) or an N-oxide, addition salt, quaternary amine, metal complex or stereochemical isomer thereof for the manufacture of a medicament for the inhibition of HCV replication. Alternatively, the present invention relates to a method for inhibiting HCV replication in warm-blooded animals, which comprises the effectiveness of a compound of formula (I) or an N-oxide, addition salt, quaternary amine, metal complex or stereochemical isomer thereof. Administering an amount.

  As used above and below, the following definitions apply unless otherwise noted.

  The term halo is generic for fluoro, chloro, bromo and iodo.

The term “polyhaloC _1-6 alkyl”, for example in polyhalo-C _1-6 alkoxy, as a group or as part of a group, is mono- or polyhalo-substituted C _1-6 alkyl, in particular at most 1, C _1-6 alkyl substituted with 2, 3, 4, 5, 6 or more halo atoms, for example methyl or ethyl with one or more fluoro atoms, for example difluoromethyl, trifluoromethyl, Defined as trifluoroethyl. Preference is given to trifluoromethyl. Also included are perfluoro C _1-6 alkyl groups, such as pentafluoroethyl, which are C _1-6 alkyl groups in which all hydrogen atoms are replaced by fluoro atoms. Within the definition of polyhaloC _1-6 alkyl, when more than one halogen atom is attached to an alkyl group, the halogen atoms can be the same or different.

As used herein, “C _1-4 alkyl” as a group or part of a group means a straight or branched saturated hydrocarbon group having 1 to 4 carbon atoms, such as methyl. , Ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-1-propyl; “C _1-6 alkyl” means a C _1-4 alkyl group and 5 or 6 Higher homologues thereof having, for example, 1-pentyl, 2-pentyl, 3-pentyl, 1-hexyl, 2-hexyl, 2-methyl-1-butyl, 2-methyl-1-pentyl, 2-ethyl Including -1-butyl, 3-methyl-2-pentyl and the like. Of interest among C _1-6 alkyl is C _1-4 alkyl.

The term “C _2-6 alkenyl” as a group or part of a group is a straight chain having a saturated carbon-carbon bond and at least one double bond and having 2 to 6 carbon atoms. And branched hydrocarbon groups such as ethenyl (or vinyl), 1-propenyl, 2-propenyl (or allyl), 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl, 2- Pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 2-methyl-2-butenyl, 2-methyl-2-pentenyl and the like are defined. Of interest among C _2-6 alkenyl is C _2-4 alkenyl.

The term “C _2-6 alkynyl” as a group or part of a group is a straight chain having a saturated carbon-carbon bond and at least one triple bond and having 2 to 6 carbon atoms and Define branched hydrocarbon groups such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 2-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl and the like . Of interest among C _2-6 alkynyl is C _2-4 alkynyl.

C _3-7 cycloalkyl is a generic term for cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

C _1-6 alkanediyl is a divalent linear and branched saturated hydrocarbon group having 1 to 6 carbon atoms, such as methylene, ethylene, 1,3-propanediyl, 1,4-butanediyl. 1,2-propanediyl, 2,3-butanediyl, 1,5-pentanediyl, 1,6-hexanediyl and the like. Of interest among C _1-6 alkanediyl is C _1-4 alkanediyl.

C _{1-6 alkoxy, C 1-6} alkyl means a _{C 1-6} alkyloxy is as defined above.

  As used herein above, the term (═O) or oxo refers to a carbonyl moiety when attached to a carbon atom, a sulfoxide moiety when attached to a sulfur atom, and two of the terms attached to a sulfur atom. If so, a sulfonyl moiety is formed. Whenever a ring or ring system is substituted with one oxo group, the carbon atom to which the oxo is attached is a saturated carbon.

The group Het is a heterocycle as defined herein and in the claims. Examples of Het are for example pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, thiazinolyl, isothiazinolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl (1,2,3-triazolyl, 1,2,2 4-triazolyl), tetrazolyl, furanyl, thienyl, pyridyl, pyrimidyl, pyridazinyl, pyrazolyl, triazinyl and the like. Of interest among the Het groups are those that are non-saturated, especially those that are aromatic. Of further interest are Het groups having one or two nitrogens.

Each of the Het groups listed in this section and in the following sections is optionally substituted with the number and type of substituents mentioned in the definition of any subgroup of compounds of formula (I) or compounds of formula (I). Can be. Some of the Het groups mentioned in this section and in the following sections can be substituted with 1, 2 or 3 hydroxy substituents. Such hydroxy-substituted rings can exist as their tautomers with keto groups. For example, the 3-hydroxypyridazine moiety can be present in its tautomer, 2H-pyridazin-3-one. When Het is piperazinyl, it is preferably in its 4-position a substituent linked to the 4-nitrogen using a carbon atom, such as 4-C _1-6 alkyl, 4-polyhalo-C _1-6 alkyl, C Substituted by _1-6 alkoxy C _1-6 alkyl, C _1-6 alkylcarbonyl, C _3-7 cycloalkyl.

  Interesting Het groups are for example pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl (1,2,3-triazolyl, 1,2,4- Triazolyl), tetrazolyl, furanyl, thienyl, pyridyl, pyrimidyl, pyridazinyl, pyrazolyl, triazinyl or any such heterocyclic ring condensed with a benzene ring, such as indolyl, indazolyl (especially 1H-indazolyl), indolinyl, quinolinyl, Tetrahydroquinolinyl (especially 1,2,3,4-tetrahydroquinolinyl), isoquinolinyl, tetrahydroisoquinolinyl (especially 1,2,3) 4- tetrahydroisoquinolinyl), including quinazolinyl, phthalazinyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoxadiazolyl, benzothiadiazolyl, benzofuranyl, benzothienyl.

  The Het group, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, 4-substituted piperazinyl are preferably linked via their nitrogen atoms (i.e. 1-pyrrolidinyl, 1-piperidinyl, 4-thiomorpholinyl, 4-morpholinyl, 1- Piperazinyl, 4-substituted 1-piperazinyl).

  It should be noted that the position of the group on any molecular moiety used in the definition can be anywhere on it as long as such moiety is chemically stable.

  Groups used in the definition of variables include all possible isomers unless otherwise specified. For example, pyridyl includes 2-pyridyl, 3-pyridyl and 4-pyridyl; pentyl includes 1-pentyl, 2-pentyl and 3-pentyl.

  If any variable occurs more than once in any constituent, each definition is independent.

  Whenever the terms "compound of formula (I)" or "present compound" or similar terms are used below, the compound of formula (I), all of its subgroups, their prodrugs, N-oxides , Addition salts, quaternary amines, metal complexes and stereochemical isomers. One embodiment comprises any subgroup of a compound of formula (I) or a compound of formula (I) as defined herein and its N-oxides, salts and possible stereoisomers. Other embodiments comprise any subgroup of compounds of formula (I) or compounds of formula (I) as defined herein, and salts and possible stereoisomers thereof.

  The compounds of formula (I) have several centers of chirality and exist as stereochemical isomers. As used herein, the term “stereochemical isomer” is made up of the same atoms bonded by the same bond permutation, but is incompatible with the three different compounds that a compound of formula (I) may have. -Define all possible compounds having a dimensional structure.

  For cases where (R) or (S) is used to specify the absolute configuration of a chiral atom within a substituent, the designation is made in consideration of the entire compound, not a separate substituent.

  Unless otherwise stated or indicated, the chemical name of a compound includes a mixture of all possible stereochemical isomers that the compound may have. The mixture can contain all diastereomers and / or enantiomers of the basic molecular structure of the compound. All stereochemical isomers of the compounds of the present invention, both in pure form or in admixture with each other, are intended to be included within the scope of the present invention.

  Pure stereoisomers of compounds and intermediates referred to herein are defined as isomers that are substantially free of other enantiomeric or diastereomeric forms of the same basic molecular structure of the compound or intermediate. . In particular, the term “stereoisomerically pure” refers to a stereoisomer excess from at least 80% (ie, a minimum of 90% of one isomer and a maximum of 10% of the other possible isomer). A compound or intermediate having a stereoisomer excess of 100% (ie, 100% of one isomer and no other isomer), more particularly having a stereoisomer excess of 90% to 100% And more particularly relates to compounds or intermediates having a stereoisomer excess of 94% to 100%, and most particularly having a stereoisomer excess of 97% to 100%. The terms “enantiomerically pure” and “diastereomerically pure” should be understood analogously, in which case the enantiomeric excess and the diastereomeric excess of the mixture in question respectively. About.

  Pure stereoisomers of the compounds and intermediates of the present invention can be obtained by application of methods known in the art. For example, enantiomers can be separated from each other by selective crystallization of their diastereomeric salts with optically active acids or bases. Examples are tartaric acid, dibenzoyl tartaric acid, ditoluoyl tartaric acid and camphorsulfonic acid. Alternatively, enantiomers can be separated by chromatographic methods using a chiral stationary phase. The pure stereochemical isomers can also be derived from the corresponding pure stereochemical isomers of suitable starting materials, provided that the reaction occurs stereospecifically. Preferably, if a particular stereoisomer is desired, the compound will be synthesized by a stereospecific manufacturing method. These methods will advantageously use enantiomerically pure starting materials.

  Diastereomeric racemates of the compounds of formula (I) can be obtained separately by conventional methods. Suitable physical separation methods that can advantageously be used are, for example, selective crystallization and chromatography, for example column chromatography.

  The absolute stereochemical configuration of the compounds of formula (I), their prodrugs, N-oxides, salts, solvates, quaternary amines or metal complexes and some of the intermediates used in their preparation is experimental Was not decided. Those skilled in the art can determine the absolute configuration of such compounds using methods known in the art such as, for example, X-ray diffraction.

The present invention is also intended to include all isotopes of atoms occurring on the present compounds.
Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and not limitation, isotopes of hydrogen include tritium and deuterium. Carbon isotopes include C-13 and C-14.

The present invention is also intended to include prodrugs of the compounds of formula (I). The term “prodrug” as used throughout the text means pharmacologically acceptable derivatives such as esters, amides and phosphates, and the biotransformation products of the resulting derivatives are defined in the compounds of formula (I). Active drug. Reference by Goodman and Gilman, which are generally described the prodrug ^{(The Pharmacological Basis of Therapeutics, 8} th ed., McGraw-Hill, Int.Ed.1992, "Biotransformation of Drugs", p.13-15) Is the content of this specification. Prodrugs preferably have excellent water solubility, improved bioavailability, and are easily metabolized in vivo to active inhibitors. Prodrugs of the compounds of the present invention can be prepared by modifying functional groups present in the compounds by routine treatment or by methods such that the modification is cleaved in vivo to yield the parent compound.

Preference is given to pharmaceutically acceptable ester prodrugs which are hydrolysable in vivo and which are derived from compounds of formula (I) having a hydroxy or carboxyl group. Esters that are hydrolysable in vivo are esters that are hydrolyzed in the human or animal body to yield the parent acid or alcohol. Suitable pharmaceutically acceptable esters for carboxy include C _1-6 alkoxymethyl esters such as methoxymethyl, C _1-6 alkanoyloxymethyl esters such as pivaloyloxymethyl, phthalidyl esters, C _{3 -8} cycloalkoxycarbonyloxy C _1-6 alkyl esters such as 1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters such as 5-methyl-1,3-dioxolen-2-onylmethyl; and C _1-6 alkoxycarbonyloxyethyl esters such as 1-methoxycarbonyloxyethyl are included and can be formed at any carboxy group in the compounds of the invention.

  In vivo hydrolysable esters of compounds of formula (I) containing hydroxy groups include inorganic esters such as phosphate esters and α-acyloxyalkyl ethers and the parent hydroxy group as a result of in vivo hydrolysis of the ester. Related compounds that provide Examples of α-acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxy-methoxy. The selection of groups that form in vivo hydrolysable esters for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N -(Dialkylaminoethyl) -N-alkylcarbamoyl (to give carbamate), dialkylaminoacetyl and carboxyacetyl. Examples of substituents on benzoyl include morpholino and piperazino linked from a ring nitrogen atom via a methylene group to the 3- or 4-position of the benzoyl ring.

  For therapeutic use, the salts of the compounds of formula (I) are those in which the counterion is pharmaceutically acceptable. However, pharmaceutically unacceptable acid and base salts may also find use, for example, in the manufacture or purification of pharmaceutically acceptable compounds. All salts, whether pharmaceutically acceptable or unacceptable, are included within the scope of the present invention.

The pharmaceutically acceptable acid and base addition salts described above are intended to include the therapeutically active non-toxic acid and base addition salt forms that the compounds of formula (I) can form. Pharmaceutically acceptable acid addition salts can be readily obtained by treatment of the base form with such suitable acids. Suitable acids are, for example, inorganic acids such as hydrohalic acids such as hydrochloric acid or hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or organic acids such as acetic acid, propanoic acid, hydroxyacetic acid, lactic acid, pyruvic acid, Oxalic acid (ie ethanedioic acid), malonic acid, succinic acid (ie butanedioic acid), maleic acid, fumaric acid, malic acid (ie hydroxybutanedioic acid), tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, Including acids such as benzenesulfonic acid, p-toluenesulfonic acid, cyclamic acid, salicylic acid, p-aminosalicylic acid and pamoic acid.

  Conversely, the salt form can be converted to the free base form by treatment with a suitable base.

  Compounds of formula (I) containing acidic protons can also be converted to their nontoxic metal or amine addition salt forms by treatment with suitable organic and inorganic bases. Suitable base salt forms include, for example, ammonium salts, alkali and alkaline earth metal salts such as lithium, sodium, potassium, magnesium, calcium salts, salts with organic bases such as benzathine, N-methyl-D-glucamine, hydrabamine. Salts as well as salts with amino acids such as arginine, lysine and the like.

  The term addition salt as used above includes the compounds of formula (I) as well as the solvates that the salts can form. Such solvates are, for example, hydrates, alcoholates and the like.

  As used herein, the term “quaternary amine” refers to a basic nitrogen of a compound of formula (I) and a suitable quaternizing agent, such as an optionally substituted alkyl halide, aryl halide or A quaternary ammonium salt is defined which a compound of formula (I) can form by reaction between an arylalkyl halide, such as methyl iodide or benzyl iodide. Other reactants with excellent leaving groups such as alkyl trifluoromethane sulfonate, alkyl methane sulfonate and alkyl p-toluene sulfonate can also be used. A quaternary amine has positively charged nitrogen. Pharmaceutically acceptable counterions include chloro, bromo, iodo, trifluoroacetate and acetate. An ion exchange resin can be used to introduce selected counter ions.

  N-oxide forms of the compounds are intended to include compounds of formula (I) in which one or several nitrogen atoms are oxidized to so-called N-oxides.

  It will be appreciated that the compounds of formula (I) can have metal binding, chelating, complexing properties and thus can exist as metal complexes or metal chelates. Such metalated derivatives of compounds of formula (I) are intended to be included within the scope of the present invention.

  Some of the compounds of formula (I) may also exist in their tautomeric form. Such forms although not explicitly indicated in the above formula are intended to be included within the scope of the present invention.

  As mentioned above, the compounds of formula (I) have several asymmetric centers. In order to more effectively point to each of these asymmetric centers, the numbering system shown in the following structural formula is used.

Asymmetric centers carbon atoms 3 of 1, 4 and 6-position and 5-membered in the ring of the macrocycle and X ', the carbon atoms 2 if R ² substituent is C _1-6 alkyl' is in CH In some cases it is present at carbon atom 1 ′. Each of these asymmetric centers can exist in their R or S configuration.

  The stereochemistry at position 1 preferably corresponds to that of the L-amino acid configuration, ie that of L-proline.

  When X is CH, the two carbonyl groups substituted at the 1 'and 5' positions of the cyclopentane ring are preferably in the trans configuration. The carbonyl substituent at the 5 'position is preferably in a configuration corresponding to the L-proline configuration. The carbonyl group substituted at the 1 'and 5' positions is preferably as depicted in the following structure:

  The compound of formula (I) contains a cyclopropyl group, as shown in the structural fragment below:

Here, C ₇ represents carbon at the 7-position, and the carbons at the 4 and 6-positions are asymmetric carbon atoms of the cyclopropane ring.

  Regardless of other possible asymmetric centers in other parts of the compound of formula (I), the presence of these two asymmetric centers indicates that the compound is a diastereomer, for example a carbon at the 7-position as shown below. Can be present as a mixture of diastereomers of the compound of formula (I) arranged syn to carbonyl or syn to amide.

  One embodiment relates to compounds of formula (I) wherein the 7-position carbon is located syn to the carbonyl. Another aspect relates to compounds of formula (I) wherein the configuration at the 4-position carbon is R. A special subgroup of compounds of formula (I) are those in which the carbon at the 7-position is arranged syn to the carbonyl and the configuration at the 4-position carbon is R.

  The compound of formula (I) may contain a proline residue (when X is N) or a cyclopentyl or cyclopentenyl residue (when X is CH or C). Preference is given to compounds of the formula (I) in which the substituent in the 1 (or 5 ') position and the carbamate substituent in the 3' position are in the trans configuration. Of particular interest are compounds of formula (I) in which the 1-position has a configuration corresponding to L-proline and the carbamate substituent at the 3 'position is in the trans configuration with respect to the 1-position. Preferably, the compound of formula (I) has the stereochemistry as shown in the structures of formulas (Ia) and (Ib) below:

One aspect of the present invention is a compound of formula (I) or a compound of formula (Ia) or any subgroup of compounds of formula (I) to which one or more of the following conditions apply: About:
(A) R ² is hydrogen;
(B) X is nitrogen;
(C) A double bond exists between carbon atoms 7 and 8.

One aspect of the present invention is a compound of formula (I) or a compound of formula (Ia), (Ib) or a compound of formula (I) to which one or more of the following conditions apply: For a compound of that subgroup:
(A) R ² is hydrogen;
(B) X is CH;
(C) A double bond exists between carbon atoms 7 and 8.

  A special subgroup of compounds of formula (I) are those represented by the following structural formulas:

  Of particular interest among the compounds of formula (Ic) and (Id) are those having the stereochemical configuration of the compounds of formula (Ia) and (Ib), respectively.

  The double bond between carbon atoms 7 and 8 in the compound of formula (I) or any subgroup of the compound of formula (I) can be in cis or trans configuration. Preferably, the double bond between carbon atoms 7 and 8 is in the cis configuration as depicted in formulas (Ic) and (Id).

  In any subgroup of compounds of formula (I) or compounds of formula (I), as depicted in formula (Ie) below, there is a double bond between carbon atoms 1 ′ and 2 ′. obtain.

  Yet another special subgroup of compounds of formula (I) are those represented by the following structural formulas:

  Of particular interest among the compounds of formula (If), (Ig) or (Ih) are those having the stereochemical configuration of the compounds of formula (Ia) and (Ib).

In (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) and (Ih), as appropriate X, n, R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined in any definition of a compound of formula (I) or a subgroup of compounds of formula (I) as defined herein. It is as it is done.

  Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (I-) defined above h) subgroups of compounds as well as any other subgroups defined herein are also prodrugs, N-oxides, addition salts, quaternary amines, metal complexes and stereochemical isomerisms of such compounds. It should be understood to include the body.

When n is 2, the moiety —CH ₂ — bracketed by “n” corresponds to ethanediyl in either a compound of formula (I) or a subgroup of compounds of formula (I). When n is 3, the moiety —CH ₂ — bracketed by “n” corresponds to propanediyl in any subgroup of compounds of formula (I) or compounds of formula (I). When n is 4, the moiety —CH ₂ — in parentheses by “n” corresponds to butanediyl in any subgroup of compounds of formula (I) or compounds of formula (I). When n is 5, the moiety —CH ₂ — in parentheses with “n” corresponds to pentanediyl in any subgroup of compounds of formula (I) or compounds of formula (I). When n is 6, the moiety —CH ₂ — bracketed by “n” corresponds to hexanediyl in any subgroup of compounds of formula (I) or compounds of formula (I). A special subgroup of compounds of formula (I) are those where n is 4 or 5.

Aspects of the present invention include
(A) R ¹ is —OR ⁶ , particularly where R ⁶ is C _1-6 alkyl, such as methyl, ethyl or tert-butyl, and most preferably R ⁶ is hydrogen; b) R ¹ is —NHS (═O) ₂ R ⁷ , particularly where R ⁷ is C _1-6 alkyl, C ₃ -C ₇ cycloalkyl or aryl, for example R ⁷ is methyl, cyclopropyl or Or (c) R ¹ is —NHS (═O) ₂ R ⁷ , particularly where R ⁷ is C _3-7 cycloalkyl substituted with C _1-6 alkyl, preferably , ^{R 7} is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, any of which have the _{C 1-4} alkyl, i.e. methyl, ethyl, propyl, isopropyl, butyl, tert- Is any of the subgroups of compounds or compound of formula (I) of the formula which is substituted with chill or isobutyl (I).

Yet another aspect of the invention is where R ¹ is —NHS (═O) ₂ R ⁷ , particularly where R ⁷ is C _1-4 alkyl, ie, cyclo substituted with methyl, ethyl, propyl or isopropyl. Either a compound of formula (I) which is propyl or a subgroup of compounds of formula (I).

Yet another aspect of the invention is a compound of formula (I) or a compound of formula (I) wherein R ¹ is —NHS (═O) ₂ R ⁷ , particularly wherein R ⁷ is 1-methylcyclopropyl One of the subgroups.

Yet another aspect of the present invention provides:
(A) R ² is hydrogen;
(B) Either a compound of formula (I) or a subgroup of compounds of formula (I), wherein R ² is C _1-6 alkyl, preferably methyl.

Aspects of the present invention include
(A) X is N, C (X is bonded through a double bond) or CH (X is bonded through a single bond), and R ² is hydrogen;
(B) a compound of formula (I) or a compound of formula (I) wherein X is C (X is linked through a double bond) and R ² is C _1-6 alkyl, preferably methyl. One of the groups.

Yet another aspect of the present invention provides:
(A) R ³ is hydrogen;
(B) R ³ is C _1-6 alkyl;
(C) Either a compound of formula (I) or a subgroup of compounds of formula (I), wherein R ³ is C _1-6 alkoxy C _1-6 alkyl or C _3-7 cycloalkyl.

A preferred embodiment of the present invention is either a compound of formula (I) or a subgroup of compounds of formula (I), wherein R ³ is hydrogen or C _1-6 alkyl, more preferably hydrogen or methyl.

An embodiment of the present invention is that R ⁴ and R ⁵ together with the nitrogen atom to which they are attached

Forming a bicyclic ring system selected from: wherein the ring system is optionally halo, hydroxy, oxo, cyano, carboxyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkoxy C ₁ A compound of formula (I) or a compound of formula (I) which can be substituted with 1 or 2 substituents independently selected from _-6 alkyl, C _1-6 alkoxycarbonyl, amino and polyhaloC _1-6 alkyl ) Is a subgroup of compounds.

Another subgroup of compounds of formula (I) is that R ⁴ and R ⁵ together with the nitrogen atom to which they are attached

Forming a bicyclic ring system selected from: wherein the ring system is optionally fluoro, chloro, hydroxy, oxo, cyano, carboxyl, methyl, ethyl, isopropyl, t-butyl, methoxy, ethoxy, isopropoxy, a compound of the formula (I) which can be substituted with one or two substituents independently selected from tert-butoxy, methoxyethyl, ethoxymethyl, methoxycarbonyl, ethoxycarbonyl, amino and trifluoromethyl, or A subgroup of any of the compounds of formula (I) as defined in the specification.

An embodiment of the present invention is that R ⁴ and R ⁵ together with the nitrogen atom to which they are attached

To form a bicyclic ring system, wherein the phenyl of the bicyclic ring system is optionally halo, hydroxy, cyano, carboxyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 A compound of formula (I) or a subgroup of compounds of formula (I) which may be substituted with one or two substituents independently selected from alkoxy-carbonyl, amino and polyhaloC _1-6 alkyl Either.

An embodiment of the present invention is that R ⁴ and R ⁵ together with the nitrogen atom to which they are attached

Forming a bicyclic ring system selected from: wherein the bicyclic ring system is optionally on the phenyl moiety, preferably at the position indicated above with a dotted line, halo, hydroxy, cyano, carboxyl, It can be substituted with 1 or 2 substituents independently selected from C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkoxy-carbonyl, amino and polyhalo-C _1-6 alkyl. Either a compound of formula (I) or a subgroup of compounds of formula (I).

An embodiment of the present invention is that R ⁴ and R ⁵ together with the nitrogen atom to which they are attached

A bicyclic ring system selected from: wherein the pyrrolidine, piperidine or morpholine ring of the bicyclic ring system is optionally C _1-6 alkyl, C _1-6 alkoxy and C _1-6 alkoxy C ₁ Either a compound of formula (I) or a subgroup of compounds of formula (I), which may be substituted with 1 or 2 substituents independently selected from _-6 alkyl.

An embodiment of the present invention is that R ⁴ and R ⁵ together with the nitrogen atom to which they are attached

To form a bicyclic ring system, wherein the phenyl of the bicyclic ring system is optionally halo, hydroxy, cyano, carboxyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 Can be substituted with one substituent independently selected from alkoxy-carbonyl, amino and polyhaloC _1-6 alkyl; and wherein the pyrrolidine, piperidine or morpholine ring of the bicyclic ring system is A compound of formula (I), optionally substituted with one substituent independently selected from C _1-6 alkyl, C _1-6 alkoxy and C _1-6 alkoxyC _1-6 alkyl, or Any of the subgroups of compounds of formula (I).

An embodiment of the present invention is that R ⁴ and R ⁵ together with the nitrogen atom to which they are attached

Forming a bicyclic ring system selected from: wherein the bicyclic ring system is optionally on the position indicated above, C _1-6 alkyl, C _1-6 alkoxy and C _1-6 alkoxy Either a compound of formula (I) or a subgroup of compounds of formula (I), which may be substituted with 1 or 2 substituents independently selected from C _1-6 alkyl.

A preferred embodiment of the present invention is that R ⁴ and R ⁵ are taken together with the nitrogen atom to which they are attached.

Either a compound of formula (I) or a subgroup of compounds of formula (I) which forms a bicyclic ring system selected from

  The compound of formula (I) consists of three building blocks P1, P2, P3. The structural unit P1 further contains a P1 'tail. In the following compound (Ic), the carbonyl group marked with an asterisk can be any part of the structural unit P2 or the structural unit P3. For chemical reasons, the building block P2 of the compound of the formula (I) in which X is C introduces a carbonyl group bonded to the 1 'position.

Linking the building blocks P1 and P2, P2 and P3, and P1 and P1 ′ (when R ¹ is —NH—SO ₂ R ⁷ ) includes the formation of an amide bond. The connection of units P1 and P3 includes double bond formation. The connection of the building blocks P1, P2 and P3 for the preparation of the compound (Ii) or (Ij) can be carried out in any given order. One of the stages involves cyclization, thereby forming a macrocycle.

  Shown below are compounds (Ii) which are compounds of formula (I) in which carbon atoms C7 and C8 are linked by a double bond and formulas in which carbon atoms C7 and C8 are linked by a single bond ( Compound (Ij) which is a compound of I). Compounds of formula (Ij) can be prepared from the corresponding compounds of formula (I-I) by reduction of double bonds in the macrocycle.

The synthetic methods described below shall be applicable to fully racemic, stereochemically pure intermediates or final products as well as stereoisomer mixtures. Racemates or stereochemical mixtures can be separated into stereoisomers at any stage in the synthesis process. In one embodiment, the intermediates and final products have the stereochemistry defined above for compounds of formula (Ia) and (Ib).

In the synthesis method described below, R ⁸ is a group

Where the dotted line indicates the bond connecting the group to the rest of the molecule.

In a preferred embodiment, the compound (I) wherein the bond between C ₇ and C ₈ is a double bond is a compound of formula (Ii) as defined above and as outlined in the following reaction scheme It can be manufactured:

  Suitable metal catalysts, such as Miller, S .; J. et al. Blackwell, H .; E. , Grubbs, R .; H. Author, J.H. Am. Chem. Soc. 118, 1996, 9606-9614; Kingsbury, J. et al. S. Harrity, J .; P. A. Bonitabus, P .; J. et al. , Hoveyda, A .; H. Author, J.H. Am. Chem. Soc. 121, 1999, 791-799; and Huang et al. Author, J.H. Am. Chem. Soc. 121, 1999, 2674-2678, a macrocycle can be formed via an olefin metathesis reaction in the presence of a Ru-based catalyst, such as the Hoveyda-Grubbs catalyst.

In air such as bis (tricyclohexylphosphine) -3-phenyl-1H-indene-1-ylideneruthenium chloride (Neolist M1 ^R ) or bis (tricyclohexylphosphine)-[(phenylthio) methylene] ruthenium (IV) dichloride A stable ruthenium catalyst can be used. Other catalysts that can be used are Grubbs first and second generation catalysts, ie, benzylidene-bis (tricyclohexylphosphine) dichlororuthenium and (1,3-bis- (2,4,6-trimethylphenyl) -2, respectively. -Imidazolidinylidene) dichloro (phenylmethylene)-(tricyclohexylphosphine) ruthenium. Of particular interest are Hoveyda-Grubbs first and second generation catalysts, which are dichloro (o-isopropoxyphenylmethylene) (tricyclohexylphosphine) -ruthenium (II) and 1,3-bis- (2,4, respectively. , 6-trimethylphenyl) -2-imidazolidinylidene) dichloro- (o-isopropoxyphenylmethylene) ruthenium. Other catalysts containing other transition metals such as Mo can also be used for this reaction.

The metathesis reaction can be carried out in a suitable solvent such as an ether such as THF, dioxane; a halogenated hydrocarbon such as dichloromethane, CHCl ₃ , 1,2-dichloroethane, etc., such as toluene. In a preferred embodiment, the metathesis reaction is performed in toluene. These reactions are performed at elevated temperatures under a nitrogen atmosphere.

  Compounds of formula (I) in which the linkage between C7 and C8 in the macrocycle is a single bond, ie compounds of formula (Ij) are derived from compounds of formula (Ii) from formula (Ii) Can be produced by reduction of the C7-C8 double bond in the compound. This reduction can be carried out by catalytic hydrogenation using hydrogen in the presence of a noble metal catalyst such as Pt, Pd, Rh, Ru or Raney nickel. Of interest is Rh on alumina. The hydrogenation reaction is preferably carried out in a solvent such as an alcohol such as methanol, ethanol or an ether such as THF or mixtures thereof. Water can also be added to these solvents or solvent mixtures.

The R ¹ group can be linked to the P1 building block at any stage of the synthesis, ie before or after the cyclization described above, or before or after the cyclization and reduction. A compound of formula (I) in which R ¹ represents —NHSO ₂ R ⁷ is represented by formula (Ik-1) and is linked by forming an amide bond between R ¹ groups to P 1 and both moieties It can be manufactured. Analogously, compounds of formula (I) wherein R ¹ represents —OR ⁶ , ie compound (Ik-2), can be prepared by linking R ¹ group to P1 by formation of an ester bond. . In one embodiment, G is a group:

As outlined in the reaction scheme below, the —OR ⁶ group is introduced at the last stage of the synthesis of compound (I).

Intermediate (2a) can be coupled with amine (2b) by any of the methods for amide formation reactions such as amide bond formation described below. In particular, (2a) is coupled with a coupling agent such as N, N′-carbonyl-diimidazole (CDI), EEDQ, IIDQ, in a solvent such as an ether such as THF or a halogenated hydrocarbon such as dichloromethane, chloroform, dichloroethane. EDCI or benzotriazol-1-yl - oxy - tris - pyrrolidino - treated with phosphonium hexafluorophosphate (commercially available as PyBOP ^R), optionally preferably after reaction with a coupling agent (2a) Can be reacted with the sulfonamide (2b). The reaction of (2a) and (2b) is preferably carried out in the presence of a base, for example a trialkylamine such as triethylamine or diisopropylethylamine or 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU). Is done. Intermediate (2a) can also be converted into an activated form, for example an activated form of the general formula G-CO-Z, where Z represents a halo or the remainder of the active ester, for example Z is an aryloxy group E.g. phenoxy, p. Nitrophenoxy, pentafluorophenoxy, trichlorophenoxy, pentachlorophenoxy, etc .; or Z can be the remainder of the mixed anhydride. In one embodiment, G-CO-Z is acid chloride (G-CO-Cl) or mixed anhydride (G-CO-O-CO-R or G-CO-O-CO-OR, R in the latter). Is, for example, C _1-4 alkyl, such as methyl, ethyl, propyl, i.propyl, butyl, t.butyl, i.butyl or benzyl. The activated form G-CO-Z is reacted with the sulfonamide (2b).

  Activation of the carboxylic acid in (2a) described in the above reaction is of the formula

To an internal cyclization reaction to an azalactone intermediate, where X, R ² , R ³ , R ⁴ , R ⁵ ,
n is as defined above, and the stereogenic center can have the stereochemical configuration as defined above, eg, as in (Ia) or (Ib). Intermediate (2a-1) can be isolated from the reaction mixture using conventional methods and the isolated intermediate (2a-1) is then reacted with (2b) or (2a- Without isolating 1), the reaction mixture containing (2a-1) can be further reacted with (2b). In one embodiment, when the reaction with the coupling agent is carried out in a water-immiscible solvent, the reaction mixture containing (2a-1) is taken up with water or water to remove all water-soluble byproducts. Can be washed with slightly basic water. The washed solution thus obtained can then be reacted with (2b) without further purification steps. On the other hand, isolation of intermediate (2a-1) causes the isolated product to react with (2b) after further purification, resulting in fewer side products and easier reaction workup. Can provide certain advantages.

Intermediate (2a) can be coupled with alcohol (2c) by an ester forming reaction. For example, (2a) and (2c) can be reacted while removing water physically, for example, by removing azeotropic water or chemically by using a dehydrating agent. Intermediate (2a) can also be converted to activated form G-CO-Z, such as the activated form described above, followed by reaction with alcohol (2c). The ester formation reaction is preferably an alkali metal carbonate or bicarbonate, such as sodium or potassium bicarbonate or a tertiary amine, such as the amines mentioned herein in connection with the amide formation reaction, in particular trialkylamines such as It is carried out in the presence of a base such as triethylamine. Solvents that can be used in the ester formation reaction are ethers such as THF; halogenated hydrocarbons such as dichloromethane, CH ₂ Cl ₂ ; hydrocarbons such as toluene; polar aprotic such as DMF, DMSO, DMA Includes solvents such as solvents.

A compound of formula (I) in which R ³ is hydrogen is represented by (I-1) and can also be removed by removal of the protecting group PG from the corresponding nitrogen-protected intermediate (3a) as in the following reaction scheme: Can be manufactured. The protecting group PG is in particular one of the nitrogen protecting groups listed below and can also be removed using the methods listed below:

The starting material (3a) in the above reaction can be prepared according to the process for the preparation of compounds of formula (I), but using an intermediate in which the group R ³ is PG.

  Compounds of formula (I) can also be obtained by reacting intermediate (4a) with amine (4b) in the presence of a carbamate-forming reagent, as outlined in the following reaction scheme in which the various groups have the meanings defined above. Can be manufactured:

  The reaction of intermediate (4a) with the carbamate forming reagent is performed in the same solvent and base used for amide bond formation as described below.

  Carbamate-forming reactions can be performed using a variety of methods, particularly by reaction of amines with alkyl chloroformates; by reaction of alcohols with carbamoyl chloride or isocyanate; through reactions involving metal complexes or acyl transfer agents. it can. For example, Greene, T .; W. and Wuts, P.A. G. M.M. "Protective groups in Organic Synthesis"; 1999; Wiley and Sons, p. See 309-348. Carbamates can be synthesized from several starting compounds including amines using carbon monoxide and certain metal catalysts. Metals such as palladium, iridium, uranium and platinum can be used as catalysts. The reported methods using carbon monoxide for the synthesis of carbamates can also be used (eg, Yoshida, Y., et al., Bull. Chem. Soc. Japan, 62, 1989, 1534; and (See Aresta, M., et al., Tetrahedron, 47, 1991, 9489).

  One method for the preparation of carbamates is the intermediate

Wherein Q is a leaving group, such as halo, especially chloro and bromo, or a group used in an active ester for amide bond formation such as those described above, such as phenoxy or substituted phenoxy, such as p. Chloro and p. Nitrophenoxy, trichlorophenoxy, pentachlorophenoxy, N-hydroxy-succinimidyl and the like. Alcohols (4a) and phosgene, thus by generating a chloroformate, or by chloro in the latter Q is to transfer to the intermediate (5a) which are intermediates of formula (5) is Q ^1, intermediate The body (4b) can be induced. In this and the following reaction methods, Q ¹ represents any of the active ester moieties as described above. Intermediate (4b) is reacted with (4a) to give compound (I).

Alcohol (4a) with carbonates ^Q 1 ^{-CO-Q 1,} for example bisphenols, bis - (substituted phenol) or bis N- hydroxy - by reaction with succinimidyl carbonate intermediates Q is ^{Q 1} (4b Intermediate (4b-1) can also be prepared:

Reagent (5a) can also be prepared from chloroformate Cl-CO-Q ¹ as follows:

  The above reaction for the preparation of reagent (4b-1) can be carried out in the presence of a base and a solvent for the formation of the amide bond mentioned below, in particular triethylamine and dichloromethane.

  Alternatively, for the preparation of compounds of formula (I), first an amide bond between building blocks P2 and P1 is formed, followed by coupling of the P3 building block to the P1 moiety in P1-P2, and Subsequently, carbamate or ester bond formation between P3 and the P2 moiety in P2-P1-P3 is carried out, and the rings are simultaneously closed.

  Yet another alternative synthetic method is the formation of an amide bond between building blocks P2 and P3, followed by coupling of building block P1 to the P3 moiety in P3-P2, and the last P1 and P1-P3- Amide bond formation between P2 in P2.

The structural units P1 and P3 can be linked to form a P1-P3 array. If necessary, the double bond connecting P1 and P3 can be reduced. The reduced or not produced P1-P3 sequence thus produced can be coupled to building block P2, and the resulting sequence P1-P3-P2 can subsequently be cyclized by formation of an amide bond.

  The structural units P1 and P3 in any of the above methods can be linked, for example, through double bond formation by olefin metathesis reaction or Wittig type reaction described below. If necessary, the double bond thus formed can be reduced analogously to that described above for the conversion of (Ii) to (Ij). It is also possible to reduce the double bond at a later stage, ie after addition of the third building block or after formation of the macrocycle. The structural units P2 and P1 are linked by amide bond formation, and P3 and P2 are linked by carbamate or ester formation.

  The tail P1 ′ can be used at any stage in the synthesis of the compound of formula (I), eg before or after coupling of building blocks P2 and P1; before or after coupling of P3 building block to P1; It can be linked to the P1 building block before or after.

  The individual building blocks can be produced first and subsequently coupled together, or alternatively the building block precursors can be coupled together and modified to the desired molecular composition at a later stage. .

  Amide bond formation can be performed using standard methods such as those used to couple amino acids in peptide synthesis. The method used to couple amino acids in peptide synthesis involves dehydratively coupling the carboxyl group of one reactant to the amino group of the other reactant to form a linked amide bond. By reacting the starting material in the presence of a coupling agent, or by converting the carboxyl functionality to an active form such as an active ester, mixed anhydride or carboxylic acid chloride or bromide Formation can be performed. A general description of such coupling reactions and the reagents used therein can be found in general textbooks on peptide chemistry such as M.M. Bodanzsky, “Peptide Chemistry”, 2nd rev. ed. , Springer-Verlag, Berlin, Germany, 1993.

  Examples of coupling reactions using amide bond formation include azide method, mixed carbonic acid-carboxylic anhydride (isobutyl chloroformate) method, carbodiimide (dicyclohexylcarbodiimide, diisopropylcarbodiimide or water-soluble carbodiimide, such as N-ethyl-N ′ -[(3-dimethylamino) propyl] carbodiimide) method, active ester method (for example, esters such as p-nitrophenyl, p-chlorophenyl, trichlorophenyl, pentachlorophenyl, pentafluorophenyl, N-hydroxysuccinimide), Woodward Reagent K-methods, 1,1-carbonyldiimidazole (CDI or N, N′-carbonyl-diimidazole) methods, phosphorus reagents or oxidation-reduction methods are included. Some of these methods can be accomplished by adding a suitable catalyst, for example, adding 1-hydroxybenzotriazole, DBU (1,8-diazabicyclo [5.4.0] undec-7-ene) or 4-DMAP in the carbodiimide method. Can be strengthened. Yet another coupling agent is (benzotriazol-1-yloxy) tris- (dimethylamino) phosphonium hexafluorophosphate alone or in the presence of 1-hydroxy-benzotriazole or 4-DMAP; or 2- (1H -Benzotoazol-1-yl) -N, N, N ', N'-tetra-methyluronium tetrafluoroborate or O- (7-azabenzotriazol-1-yl) -N, N, N', N′-tetramethyluronium hexafluorophosphate. These coupling reactions can be performed in solution (liquid phase) or solid phase.

  Preferred amide bond formation is with N-ethyloxycarbonyl-2-ethyloxy-1,2-dihydroquinoline (EEDQ) or N-isobutyloxy-carbonyl-2-isobutyloxy-1,2-dihydroquinoline (IIDQ). Done. Unlike the classical anhydride method, EEDQ and IIDQ do not require a base or low reaction temperature. Typically, the method involves reacting equimolar amounts of the carboxyl and amine components in an organic solvent (a variety of solvents can be used). EEDQ and IIDQ are added in excess and the mixture is stirred at room temperature.

  The coupling reaction is preferably in an inert solvent such as a halogenated hydrocarbon such as dichloromethane, chloroform, a dipolar aprotic solvent such as acetonitrile, dimethylformamide, dimethylacetamide, DMSO, HMPT, ether such as tetrahydrofuran (THF). Is done.

  In many cases, the coupling reaction is a suitable base such as a tertiary amine such as triethylamine, diisopropylethylamine (DIPEA), N-methyl-morpholine, N-methylpyrrolidine, 4-DMAP or 1,8-diazabicyclo [5. 4.0] Performed in the presence of undec-7-ene (DBU). The reaction temperature can range from 0 ° C. to 50 ° C., and the reaction time can range from 15 minutes to 24 hours.

  Functional groups in the structural units linked together can be protected to avoid the formation of undesirable bonds. Suitable protecting groups that can be used are described, for example, by Greene, “Protective Groups in Organic Chemistry”, John Wiley & Sons, New York, 1999, and “The Peptides: Analysis, Biosynthesis”, Synthesis. 3, Academic Press, New York, 1987.

  The carboxyl group can be protected as an ester, which can be cleaved to give the carboxylic acid. Protecting groups that can be used include 1) alkyl esters such as methyl, trimethylsilyl and tert-butyl; 2) arylalkyl esters such as benzyl and substituted benzyl; or 3) mild such as trichloroethyl and phenacyl esters Included are esters that can be cleaved by base or mild reductive means.

The amino group can be a variety of N-protecting groups such as:
1) acyl groups such as formyl, trifluoroacetyl, phthalyl and p-toluenesulfonyl;
2) aromatic carbamate groups such as benzyloxycarbonyl (Cbz or Z) and substituted benzyloxycarbonyl and 9-fluorenylmethyloxycarbonyl (Fmoc);
3) Aliphatic carbamate groups such as tert-butyloxycarbonyl (Boc), ethoxycarbonyl, diisopropylmethoxy-carbonyl and allyloxycarbonyl;
4) cyclic alkyl carbamate groups such as cyclopentyloxycarbonyl and adamantyloxycarbonyl;
5) an alkyl group such as triphenylmethyl, benzyl or substituted benzyl, for example 4-methoxybenzyl;
6) Trimethylsilyl or t. Can be protected by trialkylsilyls such as Budimethylsilyl; and 7) thiol-containing groups such as phenylthiocarbonyl and dithiasuccinoyl. Interesting amino protecting groups are Boc and Fmoc.

Preferably, the amino protecting group is cleaved before the next coupling step. Removal of the N-protecting group can be performed according to methods known in the art. If the Boc group is used, the method chosen is neat or trifluoroacetic acid in dichloromethane or HCl in dioxane or ethyl acetate. The resulting ammonium salt is then neutralized prior to coupling or in situ with a basic solution such as an aqueous buffer solution or a tertiary amine in dichloromethane or acetonitrile or dimethylformamide. When the Fmoc group is used, the reagent of choice is piperidine or substituted piperidine in dimethylformamide, but any secondary amine can be used. Deprotection is carried out at temperatures between 0 ° C. and room temperature, usually at about 15-25 ° C. or 20-22 ° C.

  Other functional groups that can interfere with the coupling reaction of the building blocks can also be protected. For example protecting the hydroxyl group as benzyl or substituted benzyl ether, eg 4-methoxybenzyl ether, benzoyl or substituted benzoyl ester, eg 4-nitrobenzoyl ester, or with a trialkylsilyl group (eg trimethylsilyl or tert-butyldimethylsilyl) can do.

  Additional amino groups can be protected by protecting groups that can be selectively cleaved. For example, when Boc is used as the α-amino protecting group, the following side chain protecting groups are suitable: the p-toluenesulfonyl (tosyl) moiety can be used for further amino group protection; Bn) ethers can be used for the protection of hydroxy groups; and benzyl esters can be used for the protection of further carboxyl groups. Alternatively, when Fmoc is chosen for α-amino protection, usually tert-butyl based protecting groups may be acceptable. For example, Boc can be used for further amino groups; tert-butyl ether can be used for hydroxyl groups; and tert-butyl ester can be used for further carboxyl groups.

  Any protecting group can be removed at any stage of the synthesis process, but preferably any protecting group of a functional group not included in the reaction stage is removed after completion of the macrocycle construction. Removal of the protecting group can be effected in any manner dictated by the choice of protecting group, which methods are well known to those skilled in the art.

  An intermediate of formula (1a) in which X is N is represented by formula (1a-1) and uses a urea-forming reaction as outlined in the following reaction scheme, starting from intermediate (5a) and converting it to carbonyl It can be prepared by reacting with an alkeneamine (5b) in the presence of an introducer.

Carbonyl (CO) introducing agents include phosgene or phosgene derivatives such as carbonyldiimidazole (CDI). In one embodiment, (5a) is reacted with a CO introducing agent in the presence of a suitable base and solvent, which can be the base and solvent used in the amide formation reaction described above. Amine (5b) is then added, thereby obtaining intermediate (1a-1) as in the above scheme. In a particular embodiment, the base is a bicarbonate such as NaHCO ₃ or a tertiary amine such as triethylamine and the solvent is an ether or halogenated hydrocarbon such as THF, CH ₂ Cl ₂ , CHCl ₃ or the like. An alternative route using similar reaction conditions involves first reacting the CO introducer with amine (5b) and then reacting the intermediate thus formed with (5a).

  Alternatively, intermediate (1a-1) can be prepared as follows:

PG ¹ is an O-protecting group, which can be any of the groups listed herein and is in particular a benzoyl or substituted benzoyl group, such as 4-nitrobenzoyl. In the latter case, especially when PG ¹ is 4-nitro with an alkali metal hydroxide (LiOH, NaOH, KOH) in an aqueous medium comprising water and a water-soluble organic solvent such as alkanol (methanol, ethanol) and THF. In the case of benzoyl, this group can be removed by reaction with LiOH.

  Intermediate (6a) is reacted with (5b) in the presence of a carbonyl introducer similar to the above, this reaction gives intermediate (6c). These are deprotected using in particular the reaction conditions mentioned above. The resulting alcohol (6d) is reacted with intermediate (4b) in the carbamate forming reaction described above for the reaction of (4a) and (4b), which reaction yields intermediate (1a-1).

An intermediate of formula (1a) where X is C is represented by formula (1a-2) and starts from intermediate (7a), which is shown in the following reaction scheme to produce an amide as described above It can be prepared by an amide-forming reaction with alkeneamine (5b) using the reaction conditions for.

  Alternatively, intermediate (1a-1) can be prepared as follows:

PG ¹ is the above O-protecting group. The same reaction conditions as above can be used: amide formation as described above, removal of PG ¹ as in the description of protecting groups and introduction of R ⁸ as in the reaction of (4a) with amine (4b).

  The intermediate of formula (2a) can be prepared by first cyclizing the open chain amide (9a) to the macrocyclic ester (9b) and then converting it to the intermediate (2a) as follows: it can:

PG ² is a carboxyl protecting group, such as one of the carboxyl protecting groups listed above, in particular C _1-4 alkyl or benzyl esters, such as methyl, ethyl or t. Butyl ester. The reaction of (9a) to (9b) is a metathesis reaction and is performed as described above. Removal of PG ² as described above gives intermediate (2a). When PG ¹ is a C _1-4 alkyl ester, it is removed by alkaline hydrolysis using eg NaOH or preferably LiOH in an aqueous solvent, eg a C _1-4 alkanol / water mixture, eg methanol / water or ethanol / water. The The benzyl group can be removed by catalytic hydrogenation.

  In an alternative synthesis, intermediate (2a) can be prepared as follows:

The PG ¹ group is chosen such that it is selectively cleavable with respect to PG ² . PG ² can be, for example, a methyl or ethyl ester, which can be removed by treatment with an alkali metal hydroxide in an aqueous medium, in which case PG ¹ is for example t. Butyl or benzyl. Alternatively, PG ² can be removed under mildly acidic conditions. It can be a butyl ester or PG ¹ can be a benzyl ester which can be removed using a strong acid or by catalytic hydrogenation, in the latter two cases, PG ¹
Is, for example, a benzoic acid ester, for example 4-nitrobenzoic acid ester.

The intermediate (10a) is first cyclized to the macrocyclic ester (10b) and the latter is deprotected by removal of the PG ¹ group to give intermediate (10c), which is reacted with the amine (4b), followed by removing the carboxyl protecting group PG ² Te. Cyclization, deprotection of PG ¹ and PG ² and coupling with (4b) are as described above.

The R ¹ group can be introduced at any stage of the synthesis, either as a last step as described above, or earlier, prior to macrocycle formation as shown in the following scheme:

In the above scheme, R ² , R ⁶ , R ⁷ , R ⁸ , X and PG ² are as defined above, and L ¹ is a P3 group

[Wherein n and R ³ are as defined above]
And when X is N, L ¹ can also be a nitrogen-protecting group (PG as defined above) and when X is C, L ¹ can also be the group —COOPG ^2a Where the group PG ^2a is a carboxyl protecting group similar to PG ² , but PG ^2a is selectively cleavable relative to PG ² . In one embodiment, PG ^2a is t. Butyl and PG ² is methyl or ethyl.

Intermediates (11c) and (11d) in which L ¹ represents group (b) correspond to intermediate (1a) and can be further processed as defined above.

Coupling of P1 and P2 building blocks The P1 and P2 building blocks are linked using an amide forming reaction according to the method described above. The P1 building block can have a carboxyl protecting group PG ² (as in (12b)) or already linked to the P1 ′ group (as in (12c)). L ² is an N-protecting group (PG) or a group (b) as defined above. L ³ is hydroxy, —OPG ¹ or a group —O—R ^{8 as} defined above. In any of the following reaction schemes, if L ³ is hydroxy before each reaction step, it is protected as the group -OPG ¹ and subsequently deprotected back to the free hydroxy function if necessary. Can do. Analogously to the above, the hydroxy functional group can be converted to the group —O—R ⁸ .

In the method of the above scheme, cyclopropyl amino acid (12b) or (12c) is coupled to the acid functional group of P2 building block (12a) by forming an amide bond according to the method described above. Intermediate (12d) or (12e) is obtained. When L ² is the group (b) in the latter, the resulting product is a P3-P2-P1 sequence that includes some of the intermediates (11c) or (11d) in the previous reaction scheme. Removal of the acid protecting group suitable use conditions in (12d) for protection group used, also coupling with subsequent above amine ^{_{H 2 N-SO 2 R 7}} (2b) or ^HOR 6 (2c) Intermediate To give the body (12e), wherein —COR ¹ is an amide or ester group. If L ² is an N-protecting group, it can be removed to give intermediate (5a) or (6a). In one embodiment, PG in this reaction is a BOC group and PG ² is methyl or ethyl. Further when L ³ is hydroxy, the starting material (12a) is Boc-L-hydroxyproline. In a particular embodiment, PG is BOC, PG ² is methyl or ethyl, and L ³ is —O—R ⁸ .

In one embodiment, L ² is the group (b) and these reactions involve the coupling of P1 to P2-P3, which results in the intermediate (1a-1) or (1a) listed above. In another embodiment, L ² is an N-protecting group PG, as defined above, and the coupling reaction yields intermediate (12d-1) or (12e-1) from which the above reaction Conditions can be used to remove the group PG to give intermediates (12-f) or (12g), respectively, which include intermediates (5a) and (6a) as defined above:

In one embodiment, the group L ³ in the above scheme represents the group —O—PG ¹ , which can be introduced onto the starting material (12a) where L ³ is hydroxy. In this case PG ¹ is chosen such that it is selectively cleavable to the group L ² which is PG.

The P2 building block in which X is C is a cyclopentane or cyclopentene derivative, which can be linked in a similar manner to the P1 building block as outlined in the following scheme, where R ¹ , R ² , L ³ , PG ² and PG ^2a are carboxyl protecting groups. PG ^2a is typically chosen such that it is selectively cleavable relative to the group PG ² . Removal of the PG ^2a group in (13c) gives intermediate (7a) or (8a), which can be reacted with (5b) above.

In one particular embodiment where X is C, R ² is H, and the carbon having X and R ² is linked by a single bond (P2 is a cyclopentane moiety), PG ^2a and L ³ are taken together To form a bond, and the P2 building block has the formula:

Indicated by.

The bicyclic acid (14a) is reacted with (12b) or (12c) analogously to the above to give (14b) and (14c), respectively, where the lactone is ring-opened to give intermediates (14c) and (14e). )give. For example, using the ester hydrolysis method using the reaction conditions described above for alkaline removal of the PG ¹ group in (9b), especially using basic conditions such as alkali metal hydroxides, eg NaOH, KOH, especially LiOH. The lactone can be opened.

  Intermediates (14c) and (14e) can be further processed as described below.

Synthesis P2 building blocks P2 building blocks contain a substituted pyrrolidine, cyclopentane or cyclopentene moieties in the group -O-R ^8.

  P2 building blocks containing a pyrrolidine moiety can be derived from commercially available hydroxyproline.

  Production of P2 building blocks containing a cyclopentane ring can be carried out as shown in the scheme below.

The bicyclic acid (17b) can be obtained, for example, from 3,4-bis (methoxycarbonyl) -cyclopentanone (17a) from Acta Chem. Scand. 46, 1992, 1277-1129, Rosenquist et al. Can be produced as described. The first step in this process involves the reduction of the keto group using a reducing agent such as sodium borohydride in a solvent such as methanol followed by hydrolysis of the ester and finally using a lactone formation method, particularly such as pyridine. Ring closure to the bicyclic lactone (17b) by using acetic anhydride in the presence of a weak base. The carboxylic acid functional group in (17b) can then be protected by the introduction of a suitable carboxyl protecting group such as the group PG ² defined above, thus giving the bicyclic ester (17c). In particular, the group PG ² is t. It is acid labile, such as a butyl group, for example using isobutene in the presence of a Lewis acid, or in the presence of a base, for example a tertiary amine such as dimethylaminopyridine or triethylamine, in a solvent such as dichloromethane. In a process using di-tert-butyl dicarbonate. The lactone ring opening of (17c) using the reaction conditions described above, particularly using lithium hydroxide, gives the acid (17d), which can be further used in a coupling reaction with the P1 building block. The free acid in (17d), preferably also be protected with an acid protecting group ^{PG 2a} that is selectively cleavable towards PG ^2, hydroxy functional group to a group -OPG ¹ or a group -O it can be converted to -R ^8. The products obtained upon removal of the group PG ² are intermediates (17g) and (17i), which correspond to intermediates (13a) or (16a) as defined above.

In the above reaction sequence, an intermediate having a specific stereochemistry can be produced by dividing the intermediate. For example, (17b) can be resolved according to methods known in the art, for example by salt formation with an optically active base or by chiral chromatography, and the resulting stereoisomers can be further purified as described above. Can be processed. The OH and COOH groups in (17d) are in the cis position. Trans analogs can be obtained by using a special reagent that reverses the stereochemistry in the reaction introducing OPG ¹ or O—R ⁸ , for example by reversing the stereochemistry at the OH-functionalized carbon, eg by applying the Mitsunobu reaction. Can be manufactured.

In one embodiment, intermediate (17d) is coupled to P1 unit (12b) or (12c) and the coupling reaction corresponds to coupling of the same P1 unit as in (13a) or (16a) using the same conditions To do. Subsequent introduction of the —O—R ⁸ -substituent as described above and subsequent removal of the acid protecting group PG ² gives intermediate (8a-1), which is a subclass of intermediate (7a) or intermediate (16a) Is part of. The reaction products of the PG ² removal can be further coupled to P3 building units. In one embodiment, PG ^{2 in} (17d) is t. Butyl, which can be removed under acidic conditions, for example using trifluoroacetic acid.

  Unsaturated P2 building blocks, ie cyclopentene rings, can be prepared as shown in the scheme below.

  J. et al. Org. Chem. 36, 1971, 1277-1285, in Dolby et al. The bromination-elimination reaction of 3,4-bis (methoxycarbonyl) cyclopentanone (17a) described by the following and subsequent reduction of the keto functional group with a reducing agent such as sodium borohydride was performed using cyclopentenol ( 19a). Selective ester hydrolysis using lithium hydroxide in a solvent such as a mixture of dioxane and water gives the hydroxy substituted monoester cyclopentenol (19b).

Unsaturated P2 building blocks where R ² can be other than hydrogen can be prepared as shown in the scheme below.

  In particular, oxidation of commercially available 3-methyl-3-buten-1-ol (20a) with an oxidizing agent such as pyridinium chlorochromate gives (20b), which is treated with acetyl chloride, for example in methanol. To the corresponding methyl ester followed by bromination with bromine to give the α-bromo ester (20c). The latter can then be condensed with the alkenyl ester (20e) obtained from (20d) by an ester forming reaction. The ester in (20e) is preferably t. Butyl ester, which can be prepared from the corresponding commercially available acid (20d) by treatment with di-tert-butyl dicarbonate in the presence of a base such as dimethylaminopyridine. Intermediate (20e) is treated with a base such as lithium diisopropylamide in a solvent such as tetrahydrofuran and reacted with (20c) to give the alkenyl diester (20f). Cyclization of (20f) by the olefin metathesis reaction performed as described above gives the cyclopentene derivative (20g). The epoxide (20h) can be obtained by performing stereoselective epoxidation of (20 g) using the Jacobsen asymmetric epoxidation method. Finally, an epoxide ring-opening reaction under basic conditions, for example by addition of a base, in particular DBN (1,5-diazabicyclo- [4.3.0] none-5-ene), gives the alcohol (20i). Optionally, the double bond in intermediate (20i) can be reduced by catalytic hydrogenation using a catalyst such as palladium on carbon to give the corresponding cyclopentane compound. t. The butyl ester can be removed to the corresponding acid, which is subsequently coupled to the P1 building block.

At any convenient stage of the synthesis of the compounds according to the invention, an —O—R ⁸ group can be introduced onto the pyrrolidine, cyclopentane or cyclopentene ring. One method is to first introduce an —O—R ⁸ group into the ring, followed by the addition of other desired building blocks, namely P1 (which can optionally have a P1 ′ tail) and P3, followed by To form a macrocycle. Another method is to couple the building blocks P2 having no —O—R ⁸ substituent with P1 and P3, respectively, and add —O—R ⁸ groups before or after macrocycle formation. . In the latter method, the P2 moiety has a hydroxy group, which can be protected by the hydroxy protecting group PG ¹ .

Analogously as described above for the synthesis of (I) starting from (4a), the hydroxy-substituted intermediate (21a) or (21b) is reacted with the intermediate (4b) to give R on the building block P2. ^Eight groups can be introduced. These reactions are shown in the following scheme, where L ² is as defined above and L ⁵ and L ^5a independently of one another represent hydroxy, a carboxy protecting group —OPG ² or —OPG ^2a , Alternatively, L ⁵ can represent a P1 group such as the group (d) or (e) defined above, or L ^5a can represent a P3 group such as the group (b) defined above. . The groups PG ² and PG ^2a are as defined above. When the groups L ⁵ and L ^5a are PG ² or PG ^2a , they are chosen such that each group is selectively cleavable relative to the other. For example, one of L ⁵ and L ^5a is a methyl or ethyl group and the other is benzyl or t. It can be a butyl group.

In one embodiment, an ^{L 2} is PG in (21a), ^{L 5} is ^{L 5a} in either a -OPG ^2, or in (21d) is -OPG ^{2, L 5} is an -OPG ² , The PG ² group is removed as described above.

In other embodiments, the group L ² is BOC, L ⁵ is hydroxy and the starting material (21a) is commercially available BOC-hydroxyproline or any other stereoisomer thereof, such as BOC- L-hydroxyproline, especially the latter trans isomer. When L ^{5 in} (21b) is a carboxyl-protecting group, it can be removed according to the method described above to give (21c). In yet another embodiment, PG in (21b-1) is Boc and PG ² is a lower alkyl ester, particularly a methyl or ethyl ester. Hydrolysis of the latter ester to the acid can be carried out by standard methods, for example by acid hydrolysis with hydrochloric acid in methanol or with alkyl metal hydroxides such as NaOH, in particular with LiOH. . In another embodiment, the hydroxy-substituted cyclopentane or cyclopentene analog (21d) is converted to (21e) which is removed by removal of the group PG ² when L ⁵ and L ^5a are -OPG ² or -OPG ^2a. It can be converted to the corresponding acid (21f). Removal of PG ^2a in (21e-1) leads to a similar intermediate.

  Intermediate (4b), which is an amino derivative, is a known compound or can be readily prepared using methods known in the art.

Synthesis of P1 building blocks Cyclopropane amino acids used in the production of P1 fragments are either commercially available or can be produced using methods known in the art.

In particular, amino-vinyl-cyclopropylethyl ester (12b) can be obtained according to the method described in WO 00/09543 or shown in the following scheme, wherein PG ² is A carboxyl protecting group as defined in:

  Treatment of a commercially available or readily obtainable imine (31a) with 1,4-dihalo-butene in the presence of a base gives (31b), which, after hydrolysis, contains carboxyl The cyclopropyl amino acid (12b) having an allyl substituent that is syn to the group is provided. Resolution of the enantiomeric mixture (12b) yields (12b-1). The resolution is performed using methods known in the art such as by enzymatic separation; crystallization with chiral acids; or chemical derivatization; or by chiral column chromatography. Intermediate (12b) or (12b-1) can be coupled to a suitable P2 derivative as described above.

The P1 building blocks for the preparation of compounds according to general formula (I) in which R ¹ is —OR ⁶ or —NH—SO ₂ R ⁷ are converted into amino acids (32a) under standard conditions for ester or amide formation. Can be prepared by reacting each with a suitable alcohol or amine. Cyclopropyl amino acid (32a) is prepared by introduction of N-protecting group PG and removal of PG ² and as outlined in the following reaction scheme, amino acid (32a) is an amide that is a subgroup of intermediate (12c). Converted to (12c-1) or ester (12c-2), where PG is as defined above.

The reaction of (32a) with amine (2b) is an amide formation method. A similar reaction with (2c) is an ester forming reaction. Both can be performed according to the method described above. This reaction provides intermediate (32b) or (32c) from which the amino protecting group is removed by standard methods such as those described above. This in turn yields the desired intermediate (12c-1). From the starting material (32a) intermediate listed above (12b), first introducing a N- protecting group PG, can subsequently be prepared by removal of the group PG ^2.

In one embodiment, the reaction of (32a) and (2b) comprises treating the amino acid with a coupling agent, such as N, N′-carbonyl-diimidazole (CDI), etc. in a solvent such as THF, followed by By reacting with (2b) in the presence of a base such as 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU). Alternatively, the amino acid is treated with (2b) in the presence of a base such as diisopropylethylamine, followed by benzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP ^R commercially The sulfonamide group can be introduced by treatment with a coupling agent such as (available).

  Intermediate (12c-1) or (12c-2) can in turn be coupled to a suitable proline, cyclopentane or cyclopentene derivative as described above.

Synthesis of P3 building blocks P3 building blocks are commercially available or can be prepared according to methods known to those skilled in the art. One of these methods is shown in the scheme below, which uses a monoacylated amine, such as trifluoroacetamide or Boc-protected amine.

In the above scheme, R together with the CO group forms an N-protecting group, in particular R is t-butoxy, trifluoromethyl; R ³ and n are as defined above and LG
Is a leaving group, in particular a halogen such as chloro or bromo.

Treatment of the monoacylated amine (33a) with a strong base such as sodium hydride followed by reaction with the reagent LG-C _5-8 alkenyl (33b), in particular halo C _5-8 alkenyl, to give the corresponding protected amine (33c) is generated. Deprotection of (33c) gives (5b), which is the building block P3. Deprotection depends on the functional group R, and thus when R is t-butoxy, the corresponding Boc-protected amine can be deprotected using an acid treatment such as trifluoroacetic acid. Alternatively, when R is, for example, trifluoromethyl, removal of the R group is performed using a base, such as sodium hydroxide.

The following scheme shows yet another method for the preparation of P3 building blocks, namely Gabriel synthesis of primary C _5-8 alkenylamines, wherein phthalimide (34a) is defined as above with a base such as NaOH or KOH and This can be done by treatment with (33b) as described, followed by hydrolysis of the intermediate N-alkenylimide to produce the primary C _5-8 alkenylamine (5b-1).

  In the above scheme, n is as defined above.

  Compounds of formula (I) can be converted into each other according to functional group conversion reactions known in the art. For example, an amino group can be N-alkylated, a nitro group can be reduced to an amino group, and a halo atom can be exchanged for another halo.

  The compound of formula (I) can be converted to the corresponding N-oxide form according to methods known in the art for converting trivalent nitrogen to its N-oxide form. The N-oxidation reaction can generally be carried out by reacting the starting material of formula (I) with a suitable organic or inorganic peroxide. Suitable inorganic peroxides include, for example, hydrogen peroxide, alkali metal or alkaline earth metal peroxides such as sodium peroxide, potassium peroxide; suitable organic peroxides are peroxy acids such as benzene carboperoxo acid. Or a halo-substituted benzene carboperoxo acid such as 3-chlorobenzene carboperoxo acid, peroxoalkanoic acid such as peroxoacetic acid, alkyl hydroperoxide such as t-butyl hydro-peroxide. Suitable solvents are, for example, water, lower alcohols such as ethanol, hydrocarbons such as toluene, ketones such as 2-butanone, halogenated hydrocarbons such as dichloromethane and mixtures of such solvents.

  By applying methods known in the art, pure stereochemical isomers of compounds of formula (I) can be obtained. Diastereomers can be separated by physical methods such as selective crystallization and chromatographic methods such as countercurrent distribution, liquid chromatography and the like.

Compounds of formula (I) can be obtained as racemic mixtures of enantiomers, which can be separated from each other according to resolution methods known in the art. Racemic compounds of formula (I) that are sufficiently basic or acidic can be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid or chiral base, respectively. The diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali or acid. Another way of separating the enantiomeric forms of the compounds of formula (I) involves liquid chromatography, in particular liquid chromatography using a chiral stationary phase. The pure stereochemical isomers can also be derived from the corresponding pure stereochemical isomers of suitable starting materials provided that the reaction occurs stereospecifically. Preferably, if a particular stereoisomer is desired, the compound can be synthesized by stereospecific production methods. These processes can advantageously use enantiomerically pure starting materials.

  In yet another aspect, the present invention provides a therapeutically effective compound of any of the compounds of formula (I) as defined herein or a subgroup of compounds of formula (I) as defined herein. And a pharmaceutical composition comprising a pharmaceutically acceptable carrier. In this regard, a therapeutically effective amount is one that acts prophylactically, stabilizes or reduces viral infections, and in particular HCV viral infections, in infected patients or patients at risk of infection. The amount is sufficient to cause In yet another aspect, the present invention relates to a method of preparing a pharmaceutical composition as defined herein, which comprises a pharmaceutically acceptable carrier as defined herein as a compound of formula (I) Or intimately mixing with a therapeutically effective amount of a compound of any of the subgroups of compounds of formula (I) as defined herein.

  Thus, the compounds of the invention or any subgroup thereof can be prepared in various pharmaceutical forms for administration purposes. Suitable compositions can include all compositions commonly used for systemic administration of drugs. For the preparation of the pharmaceutical compositions of the present invention, an effective amount as the active ingredient of a particular compound, which can optionally be in the form of an addition salt or in a metal complex, is in close contact with a pharmaceutically acceptable carrier. Combined in such a mixture, the carrier can take a wide variety of forms depending on the form of preparation desired for administration. Desirably these pharmaceutical compositions are in unit dosage forms suitable for administration, particularly by oral, rectal, transdermal or parenteral injection. For example, in the preparation of compositions in oral dosage forms, in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions and solutions in any conventional pharmaceutical medium, water, glycols, Oils, alcohols and the like; or in the case of powders, pills, capsules and tablets, solid carriers such as starches, sugars, kaolins, lubricants, binders, disintegrants and the like can be used. Because of their ease of administration, tablets and capsules provide the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise at least a majority of sterile water, but can contain other ingredients, for example, to aid solubility. For example, an injectable solution can be prepared in which the carrier comprises saline, glucose solution or a mixture of saline and glucose solution. Injectable suspensions can also be prepared, in which case suitable liquid carriers, suspending agents and the like can be employed. Also included are solid form preparations that are intended to be converted, shortly before use, to liquid form preparations. In compositions suitable for transdermal administration, the carrier may optionally comprise a penetration enhancer and / or a suitable wetting agent, optionally in any of a small proportion that does not introduce significant adverse effects on the skin. Can be combined with suitable additives of the nature.

  The compounds of the present invention can also be administered via oral inhalation or insufflation by methods and preparations used in the art for administration via this method. Thus, in general, the compounds of the invention can be administered to the lung in the form of a solution, suspension or dry powder, with solutions being preferred. Any system developed for the delivery of solutions, suspensions or dry powders via oral inhalation or insufflation is suitable for administration of the compounds.

The invention thus also provides a pharmaceutical composition adapted for administration by inhalation or insufflation through the mouth comprising a compound of formula (I) and a pharmaceutically acceptable carrier. Preferably, the compounds of the invention are administered via inhalation of the solution in a nebulized or aerosolized dosage.

  It is especially advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. Unit dosage forms as used herein refer to physically separated units suitable as a single dosage, each unit being a predetermined amount of activity calculated to produce the desired therapeutic effect. The ingredients are included with the necessary pharmaceutical carrier. Examples of such unit dosage forms are tablets (including chopped or coated tablets), capsules, pills, suppositories, powder packages, wafers, injectable solutions or suspensions, etc., as well as multiple of them separated is there.

  The compounds of formula (I) exhibit antiviral properties. Viral infections and related diseases that can be treated using the compounds and methods of the present invention include HCV and other pathogenic flaviviruses such as yellow fever, dengue fever (types 1-4), St. Louis encephalitis, Japanese encephalitis, Infections caused by Mary Valley encephalitis, West Nile virus, and Kunjin virus are included. Diseases associated with HCV include progressive liver fibrosis, necrosis leading to inflammation and cirrhosis, end-stage liver disease and HCC; for other pathogenic flaviviruses, diseases include yellow fever, dengue fever, hemorrhagic fever and Encephalitis is included. In addition, several compounds of the invention are active against mutant strains of HCV. In addition, many of the compounds of the present invention exhibit favorable pharmacokinetic aspects and have attractive properties in terms of bioavailability including acceptable half-life, AUC (area under the curve) and peak values. And there are no undesirable phenomena such as inadequate rapid initiation and tissue retention.

The in vitro antiviral activity against HCV of compounds of formula (I) was determined by Krieger et al.
al. Journal of Virology 75: 2001, 4614-4624, and further illustrated in the Examples section, Lohmann et al. Author, Science 285: 1999, examined in a cellular HCV replicon system based on 110-113. This model is not a complete infection model for HCV, but is widely accepted as the most robust and effective model of autonomous HCV RNA replication currently available. Compounds that exhibit anti-HCV activity in this cell model are considered candidates for further development in the treatment of HCV infection in mammals. It is recognized that it is important to distinguish compounds that specifically interfere with HCV function from compounds that exert cytotoxicity or static cell effects in the HCV replicon model and ultimately reduce HCV RNA or chain reporter enzyme levels. Will. Assays for the assessment of cellular cytotoxicity based on the activity of mitochondrial enzymes using a fluorescent redox dye, such as resazurin, are known in the art. In addition, there are cell counter screens for the assessment of non-selective inhibition of linked reporter gene activity, such as firefly luciferase. In a suitable cell type, a luciferase reporter gene whose expression depends on a constitutively active gene promoter can be provided by stable transfection, and such cells can be reversed for removal of non-selective inhibitors. It can be used as a selective substance.

  Due to the antiviral properties of the compounds of formula (I) or any subgroup thereof, their prodrugs, N-oxides, addition salts, quaternary amines, metal complexes and stereochemical isomers, in particular Because of their anti-HCV properties, they are useful in the treatment of patients who have experienced viral infections, particularly HCV infections, as well as for the prevention of these infections. In general, the compounds of the present invention may be useful in the treatment of warm-blooded animals infected with viruses, particularly flaviviruses such as HCV.

  Accordingly, the compounds of the present invention or any subgroup thereof can be used as drugs. Use as a medicament or method of treatment includes systemically administering to a patient infected or susceptible to viral infection, an amount effective to control a condition associated with viral infection, particularly HCV infection. It becomes.

  The invention also relates to the use of the present compounds or any subgroup thereof in the manufacture of a medicament for the treatment or prevention of viral infections, in particular HCV infection.

  The invention further relates to a method for the treatment of warm-blooded animals infected with viruses, in particular HCV or at risk of being infected with viruses, in particular HCV, which comprises a compound of formula (I) as defined herein or a Administering an anti-virally effective amount of a compound of any of the subgroups of compounds of formula (I) as defined in the specification.

  Use of previously known anti-HCV compounds, such as interferon-α (IFN-α), polyethylene glycolated interferon-α and / or a combination of ribavirin and a compound of formula (I) as agents in combination therapy You can also. The term “combination therapy” refers to the (a) compound of formula (I) essential as a combination preparation for simultaneous, separate or sequential use in the treatment of HCV infection, in particular the treatment of HCV infection, and (B) relates to products optionally containing other anti-HCV compounds.

  Anti-HCV compounds include agents selected from HCV polymerase inhibitors, HCV protease inhibitors, inhibitors of other targets in the HCV life cycle and immunomodulators, antiviral agents, and combinations thereof.

  HCV polymerase inhibitors include, but are not limited to, NM283 (valopicitabine), R803, JTK-109, JTK-003, HCV-371, HCV-086, HCV-796 and R-1479.

  Inhibitors of HCV protease (NS2-NS3 inhibitor and NS3-NS4A inhibitor) include compounds of WO 02/18369 pamphlet (for example, pages 273, 9-22 and 274, lines 4 to 276, line 11). See B); BILN-2061, VX-950, GS-9132 (ACH-806), SCH-503034 and SCH-6. Further drugs that can be used are WO 98/17679, WO 00/056331 (Vertex); WO 98/22496 (Roche); WO 99/07734. Brochures, (Boehringer Ingelheim), WO 2005/073216, WO 200507195 (Medivir) and structurally similar drugs.

  Inhibitors of other targets in the HCV life cycle include NS3 helicase; metalloprotease inhibitors; antisense oligonucleotide inhibitors such as ISIS-14803, AVI-4065; siRNA's such as SIRPLEX-140-N; vectors -Coding short hairpin RNA (shRNA); DNAzyme; HCV specific ribozyme such as heptazyme, RPI. 13919 etc .; entry inhibitors such as HepeX-C, HuMax-HepC, etc .; alpha glucosidase inhibitors such as celgosivir, UT-231B etc .; KPE-02003002; and BIVN 401.

Immunomodulatory agents; alpha-interferon, beta-interferon, .gamma.-interferon, .omega.-interferon, natural and recombinant interferon isoform compounds containing, for example, ^{Intron A R, Roferon-A R} , Canferon-A300 R, Advaferon R , Infergen ^R , Humoferon ^R , Sumiferon MP ^R , Alfaferone ^R , IFN-beta ^R , Feron ^{R and the} like; polyethylene glycol derivatized interferon compounds such as PEG interferon-α-2a (Pegasys ^R ) -α interferon 2b (PEG-Intron ^R), polyethylene glycol derivatized IFN-α-con1; interferon of Long-acting preparations and derivatives of products, such as albumin-fusion interferon albferon alpha; compounds that stimulate the synthesis of interferon in cells, such as resiquimod; interleukins; type 1 helper T cell responses Compounds that enhance expression, such as SCV-07; TOLL-like receptor agonists such as CpG-10101 (actilon), isatoribine, etc .; thymosin alpha-1; ANA-245; ANA-246; histamine Dihydrochloride; propagermanium; tetrachlorodecaoxide; ampligen; IMP-321; KRN-7000; antibodies such as cibacil (civa) ir), etc. XTL-6865; and preventive and therapeutic vaccines, for example Inno Vac C, although etc. HCV E1E2 / MF59, not limited to these.

  Other antiviral agents include ribavirin, amantadine, viramidine, nitazoxanide; terbivudine; NOV-205; a widespread inhibitor of taribavirin; an internal ribosome inhibitor; For example, IMPDH inhibitors (eg, US Pat. No. 5,807,876, US Pat. No. 6,498,178, US Pat. No. 6,344,465, US Pat. No. 6,054,472). Specification, WO 97/40028 pamphlet, WO 98/40381 pamphlet, WO 00/56331 pamphlet, and mycophenolic a id) and derivatives thereof and including VX-950, merimepodib (VX-497), VX-148 and / or VX-944); or any combination of the above Not limited to these.

  Thus, for the control or treatment of HCV infection, the compounds of formula (I) are treated with, for example, interferon-α (IFN-α), polyethylene glycol derivatized interferon-α and / or ribavirin and antibodies targeting HCV epitopes. It can be co-administered in combination with drugs, small interfering RNA (Si RNA), ribozymes, DNAzymes, antisense RNA, such as small molecule antagonists of NS3 protease, NS3 helicase and NS5B polymerase.

  The present invention therefore relates to the use of a compound of formula (I) as defined above or any subgroup thereof for the manufacture of a medicament useful for inhibiting HCV activity in a mammal infected with HCV virus, wherein said The drugs are used in combination therapy, which preferably comprises a compound of formula (I) and other HCV inhibitory compounds such as (polyethylene glycol derivatized) IFN-α and / or ribavirin.

  In yet another aspect, there is provided a combination of a compound of formula (I) and an anti-HIV compound as defined herein. The latter are preferably HIV inhibitors that have a positive effect on improving bioavailability in drug metabolism and / or pharmacokinetics. An example of such an HIV inhibitor is ritonavir.

  Accordingly, the present invention comprises (a) an HCV NS3 / 4a protease inhibitor of formula (I) or a pharmaceutically acceptable salt thereof; and (b) ritonavir or a pharmaceutically acceptable salt thereof. Provide further combinations.

  The compound ritonavir and its pharmaceutically acceptable salts and methods for its preparation are described in WO 94/14436. Regarding preferred dosage forms of ritonavir, US Pat. No. 6,037,157 and documents cited therein; US Pat. No. 5,484,801, US Pat. No. 08 / 402,690 and See WO 95/07696 pamphlet and WO 95/09614 pamphlet. Ritonavir has the following formula:

Have

  In yet another embodiment, comprising (a) an HCV NS3 / 4a protease inhibitor of formula (I) or a pharmaceutically acceptable salt thereof; and (b) ritonavir or a pharmaceutically acceptable salt thereof. The combination further comprises an additional anti-HCV compound selected from the compounds described herein.

  In one embodiment of the invention, the method comprises combining the HCV NS3 / 4a protease inhibitor of formula (I) or a pharmaceutically acceptable salt thereof and ritonavir or a pharmaceutically acceptable salt thereof. Methods for preparing the combinations described herein are provided. Another aspect of the present invention provides a method wherein the combination comprises one or more additional agents described herein.

  The combination of the present invention can be used as a medicine. The pharmaceutical use or method of treatment comprises systemically administering to an HCV-infected patient an amount effective for controlling conditions associated with HCV and other pathogenic flavi- and pestiviruses. Ultimately, the combinations of the present invention are useful for the treatment, prevention or control of HCV infection or infection-related diseases in mammals, particularly for the treatment of conditions associated with HCV and other pathogenic flavi- and pestiviruses. It can be used in the manufacture of a medicament.

  In one aspect of the invention there is provided a pharmaceutical composition comprising a combination according to any one of the aspects described herein and a pharmaceutically acceptable excipient. In particular, the invention relates to (a) a therapeutically effective amount of an HCV NS3 / 4a protease inhibitor of formula (I) or a pharmaceutically acceptable salt thereof, (b) ritonavir or a pharmaceutically acceptable salt thereof. Provided is a pharmaceutical composition comprising a therapeutically effective amount of the resulting salt and (c) a pharmaceutically acceptable excipient. Optionally, the pharmaceutical composition further comprises an additional agent selected from HCV polymerase inhibitors, HCV protease inhibitors, inhibitors of other targets in the HCV life cycle and immunomodulators, antiviral agents, and combinations thereof Can be included.

  The composition can be prepared into suitable pharmaceutical dosage forms, such as those described above. Each of the active ingredients can be prepared separately and the formulation can be co-administered, or a single formulation containing both and, if necessary, further active ingredients can be provided.

  As used herein, the term “composition” is intended to encompass a product comprising a defined component as well as a product that results directly or indirectly from a combination of defined components. ing.

  In one embodiment, the combinations provided herein can also be prepared as a combined preparation for simultaneous, separate or sequential use in HIV treatment. In such cases, the compound of general formula (I) or any subgroup thereof is prepared in a pharmaceutical composition containing other pharmaceutically acceptable excipients, and ritonavir is prepared by other pharmaceutical agents. Prepared separately in a pharmaceutical composition containing a pharmaceutically acceptable excipient. Conveniently, these two separate pharmaceutical compositions can be part of a kit for simultaneous, separate or sequential use.

  Thus, the individual components of the combination of the present invention can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms. Accordingly, the present invention should be understood to encompass the management of all such simultaneous or alternating treatments and the term “administering” should be construed accordingly. In a preferred embodiment, separate dosage forms are administered about simultaneously.

  In one embodiment, the combination of the present invention provides the bioavailability of an HCV NS3 / 4a protease inhibitor of formula (I) when administered alone with the HCV NS3 / 4a protease inhibitor of formula (I). Contains an amount of ritonavir or a pharmaceutically acceptable salt thereof that is sufficient to clinically improve bioavailability.

In another aspect, the combination of the present invention provides an HCV NS3 / 4a protease inhibitor of formula (I) selected from t _1/2 , C _min , C _max , C _ss , AUC at 12 hours or AUC at 24 hours. Sufficient to improve at least one of the pharmacokinetic variables relative to the at least one pharmacokinetic variable when the HCV NS3 / 4a protease inhibitor of formula (I) alone is administered. Containing an amount of ritonavir or a pharmaceutically acceptable salt thereof.

  Yet another aspect relates to a method for improving the bioavailability of an HCV NS3 / 4a protease inhibitor, which includes a therapeutically effective amount of each component of the combination in a patient in need of such improvement. Administering a combination as defined herein comprising:

In yet another aspect, the invention provides a drug of the formula (I) HCV NS3 / 4a protease inhibitor selected from t _1/2 , C _min , C _max , C _ss , AUC at 12 hours or AUC at 24 hours Regarding the use of ritonavir or a pharmaceutically acceptable salt thereof as at least one enhancer of kinetic variables; provided that the use is not carried out in the human or animal body.

  As used herein, the term “patient” refers to an animal, preferably a mammal, most preferably a human, that has been the subject of treatment, observation or experimentation.

Bioavailability is defined as the rate at which systemic circulation is reached in the dose administered. t _1/2 indicates the half-life or the time required for the plasma concentration to drop to half its initial value. C _ss is the steady state concentration, ie the concentration at which the rate of drug absorption is equal to the rate of removal. C _min is defined as the lowest (minimum) concentration measured during the dosing interval. C _max indicates the highest (maximum) concentration measured during the dosing interval. AUC is defined as the area under the plasma concentration-time curve for a defined time.

  The combinations of the present invention can be administered to humans within dosage ranges specific for each component contained in the combination. The components contained in the combination can be administered together or individually. NS3 / 4a protease inhibitor of formula (I) or any subgroup thereof and ritonavir or a pharmaceutically acceptable salt or ester thereof in a dosage of 0.02 to 5.0 grams per day You can have a level.

  When administered in combination with an HCV NS3 / 4a protease inhibitor of formula (I) and ritonavir, the weight ratio of HCV NS3 / 4a protease inhibitor of formula (I) to ritonavir is suitably about 40: 1 to about 1 : 15 or about 30: 1 to about 1:15 or about 15: 1 to about 1:15, typically about 10: 1 to about 1:10, and more typically about 8: 1 to about 1: : Within the range of 8. About 6: 1 to about 1: 6 or about 4: 1 to about 1: 4 or about 3: 1 to about 1: 3 or about 2: 1 to about 1: 2 or about 1.5: 1 to about 1: A weight ratio of HCV NS3 / 4a protease inhibitor of formula (I) to ritonavir in the range of 1.5 is also useful. In one aspect, the amount by weight of the HCV NS3 / 4a protease inhibitor of formula (I) is equal to or greater than that of ritonavir, wherein the HCV NS3 / 4a protease inhibitor of formula (I) vs. ritonavir. The weight ratio is suitably within the range of about 1: 1 to about 15: 1, typically about 1: 1 to about 10: 1, and more typically about 1: 1 to about 8: 1. is there. From about 1: 1 to about 6: 1 or from about 1: 1 to about 5: 1 or from about 1: 1 to about 4: 1 or from about 3: 2 to about 3: 1 or from about 1: 1 to about 2: 1 or Also useful are weight ratios of the HCV NS3 / 4a protease inhibitor of formula (I) to ritonavir in the range of about 1: 1 to about 1.5: 1.

  As used herein, the term “therapeutically effective amount” refers to an organism in a tissue, system, animal or human that is being sought by a researcher, veterinarian, physician or other clinician from the perspective of the present invention. Means the amount of an active compound or ingredient or pharmaceutical agent that elicits a pharmacological or medical response, which includes a reduction in the symptoms of the disease being treated. Since the present invention relates to a combination comprising two or more agents, a “therapeutically effective amount” is taken together so that the combined effect elicits the desired biological or medical response. Is the amount of the drug. For example, a therapeutically effective amount of a composition comprising (a) a compound of formula (I) and (b) ritonavir has a combined effect that when taken together is therapeutically effective ( The amount of the compound of I) and the amount of ritonavir.

  In general, a daily antivirally effective amount would be 0.01 mg to 500 mg per kg body weight, more preferably 0.1 mg to 50 mg per kg body weight. It may be appropriate to administer the required dosage as 1, 2, 3, 4 or more (sub-) dosages at suitable intervals throughout the day. The (sub-)-dosage may be prepared as a unit dosage form containing, for example, 1-1000 mg per unit dosage form, and especially 5-200 mg of active ingredient.

The exact dosage and frequency of administration will depend on the particular compound of formula (I) used, the particular condition being treated, the severity of the condition being treated, as specified by those skilled in the art The patient's age, weight, gender, degree of disability and general physical conditions and other medications the patient may be taking. It is further apparent that the effective daily dose can be reduced or increased depending on the response of the patient being treated and / or depending on the evaluation of the physician prescribing the compound of the invention. It is. Accordingly, the daily effective dose range referred to above is merely a guide.

  According to one embodiment, the HCV NS3 / 4a protease inhibitor of formula (I) and ritonavir can be co-administered once or twice daily, preferably orally, wherein the formula (I ) Is about 1 to about 2500 mg, and the amount of ritonavir per dose is 1 to about 2500 mg. In another embodiment, the dose per dose for co-administration once or twice daily is about 50 to about 1500 mg of the compound of formula (I) and about 50 to about 1500 mg of ritonavir. In yet another embodiment, the dose per dose for co-administration once or twice daily is about 100 to about 1000 mg of the compound of formula (I) and about 100 to about 800 mg of ritonavir. In still yet another embodiment, the amount per dose for co-administration once or twice daily is about 150 to about 800 mg of the compound of formula (I) and about 100 to about 600 mg of ritonavir. In still yet another embodiment, the dose per dose for co-administration once or twice daily is about 200 to about 600 mg of the compound of formula (I) and about 100 to about 400 mg of ritonavir. In still yet another embodiment, the dose per dose for co-administration once or twice daily is about 200 to about 600 mg of the compound of formula (I) and about 20 to about 300 mg of ritonavir. In still yet another embodiment, the dose per dose for co-administration once or twice daily is about 100 to about 400 mg of the compound of formula (I) and about 40 to about 100 mg of ritonavir.

  Typical combinations of compound of formula (I) (mg) / ritonavir (mg) for dosing once or twice a day are 50/100, 100/100, 150/100, 200/100, 250 / 100, 300/100, 350/100, 400/100, 450/100, 50/133, 100/133, 150/133, 200/133, 250/133, 300/133, 50/150, 100/150 150/150, 200/150, 250/150, 50/200, 100/200, 150/200, 200/200, 250/200, 300/200, 50/300, 80/300, 150/300, 200 / 300, 250/300, 300/300, 200/600, 400/600, 600/600, 800/600, 000/600, 200/666, 400/666, 600/666, 800/666, 1000/666, 1200/666, 200/800, 400/800, 600/800, 800/800, 1000/800, 1200 / 800, 200/1200, 400/1200, 600/1200, 800/1200, 1000/1200 and 1200/1200 are included. Other exemplary combinations of compound of formula (I) (mg) / ritonavir (mg) for dosing once or twice daily include 1200/400, 800/400, 600/400, 400/200 600/200, 600/100, 500/100, 400/50, 300/50 and 200/50.

  In one aspect of the invention, a composition effective to treat HCV infection or inhibit NS3 protease of HCV; and that the composition can be used for the treatment of infection by hepatitis C virus. Provided is a product comprising a packaging material comprising a label as indicated; wherein the composition comprises a compound of formula (I) or any subgroup thereof or a combination described herein.

Another aspect of the invention is an amount effective for use as a standard or reagent in a test or assay to determine the ability of a potential agent to inhibit HCV NS3 / 4a protease, HCV growth or both. A combination of a compound of (I) or any subgroup thereof or an HCV NS3 / 4a protease inhibitor of formula (I) or a pharmaceutically acceptable salt thereof and ritonavir or a pharmaceutically acceptable salt thereof To a kit or container comprising a combination according to the invention. This aspect of the invention may find its use in pharmaceutical research programs.

  The compounds and combinations of the present invention can be used in high-throughput target-analyte assays, such as assays for measuring the effectiveness of the combination in HCV treatment.

  The following examples are intended to illustrate the invention and are not intended to limit the invention to the examples.

General: LC / MS analysis was performed on a Waters Alliance 2795 HT coupled to a Micromass ZMD mass spectrometer using electrospray ionization in positive mode.

Eluent: A: water, 0.1% TFA, B: acetonitrile, 0.1% TFA. Detection: UV (diode array: 210-300 nm). Gradient: Method A: 20 to 70% B in A (1.5 mL min- ¹ ) over 5 min. Method B: 30-80% B in A (1.5 mL min- ¹ ) over 5 minutes. Method C: 40 to 80% B in A over 5 minutes (1.5 mL min- ¹ ). Method D: 50-90% B in A over 5 minutes (1.5 mL min- ¹ ). Method E: 20 to 70% B in A (0.9 mL min ⁻¹ ) over 2.5 min. Method F: 30-80% B in A (0.9 mL min ⁻¹ ) over 2.5 min. Method G: 40-80% B in A (0.9 mL min ⁻¹ ) over 2.5 min. Method H: 50-90% B in A (0.9 mL min ⁻¹ ) over 2.5 min. Column: Methods AD: Phenomonex, Synergi MAX RP-80A column (5.0 cm, 4.6 mmφ, 4 μm). Methods EH: Phenomenex, Synergi MAX RP-80A column (3.0 cm, 3.0 mmφ, 4 μm).

Example 1 Synthesis of 1-[(3-oxo-2-aza-bicyclo [2.2.1] heptane-5-carbonyl) -amino] -2-vinyl-cyclopropanecarboxylic acid ethyl ester (3)

To a solution of 1 (857 mg, 5.5 mmol) in DMF (14 mL) and DCM (25 mL) at room temperature was added 2 (1.15 g, 6.0 mmol), HATU (2.29 g, 6.0 mmol) and DIPEA (3.82 mL, 22 mmol) was added. The reaction N ₂ - was stirred for 1 hour at ambient temperature under an atmosphere. LC / MS analysis showed complete conversion and the reaction mixture was concentrated in vacuo. The residue was re-dissolved in DCM (100 mL) and 0.1 M HCl (aq) and the phases were separated. The organic phase was washed with NaHCO ₃ (aq) and brine, dried (MgSO ₄ ) and filtered. Removal of the solvent in vacuo gave the target compound 3 (1.6 g, 99%). LC / MS (Method A): t _R = 2.46 min,> 95%, m / z (ESI ⁺ ) = 294 (MH ⁺ )

Example 2 : Synthesis of 2- (1-ethoxycarbonyl-2-vinylcyclopropylcarbamoyl) -4-hydroxy-cyclopentanecarboxylic acid diisopropylethylamine salt (4)

To a solution of 3 (800 mg, 2.73 mmol) in water (15 mL) in a 20 mL microwave reaction vessel was added DIPEA (1.2 mL, 6.8 mmol) and a stir bar. The reaction vessel was sealed and the immiscible slurry was vigorously shaken before being inserted into the microwave oven cavity. After 1 minute pre-stirring, the reaction was irradiated to a set temperature of 100 ° C. for 40 minutes. After cooling to 40 ° C., the clear solution was concentrated in vacuo and the residual brown oil was co-evaporated 3 times with MeCN to remove residual water. The crude product 4 in the form of DIPEA salt was immediately advanced to the next reaction. LC / MS (Method A): t _R = 1.29 min,> 95%, m / z (ESI ⁺ ) = 312 (MH ⁺ )

Example 3 Synthesis of 1-{[2- (hex-5-enylmethylcarbamoyl) -4-hydroxycyclopentanecarbonyl] amino} -2-vinylcyclopropanecarboxylic acid ethyl ester (6)

Crude compound 4 (5.5 mmol) was dissolved in DCM (50 mL) and DMF (14 mL) followed by HATU (2.09 g, 5.5 mmol), 5 (678 mg, 6.0 mmol) and DIPEA ( 3.08 mL, 17.5 mmol) was added at room temperature. The reaction was stirred at ambient temperature for 1 hour. LC / MS analysis showed complete conversion and the reaction mixture was concentrated in vacuo. The residue was redissolved in EtOAc (100 mL) and the organic phase was washed with 0.1 M HCl (aq), K ₂ CO ₃ (aq) and brine, dried (MgSO ₄ ) and filtered. Evaporation of the solvent in vacuo gave an oil that was purified by flash chromatography (silica, EtOAc: MeOH) to give the desired compound 6 (1.65 g, 74%). TLC (silica): MeOH: EtOAc 5:95, R _f = 0.5; LC / MS (Method A): t _R = 3.44 min,> 95%, m / z (ESI ⁺ ) = 407 (MH ⁺ )

Example 4 Synthesis of 1-{[2- (hex-5-enylmethylcarbamoyl) -4-hydroxycyclopentane-carbonyl] amino} -2-vinylcyclopropanecarboxylic acid (7)

Compound 6 (493 mg, 1.21 mmol) was dissolved in DMF (1 mL) and transferred to a 20 mL microwave reaction vessel. An aqueous LiOH solution (2M, 10.5 mL) and a stir bar were then added. The reaction vessel was sealed and the immiscible slurry was vigorously shaken before being inserted into the microwave cavity. The reaction was irradiated at 130 ° C. for 30 minutes. The reaction mixture was cooled to 40 ° C. and the clear solution was acidified to pH 2 with aqueous HCl (1M, 24 mL) and extracted three times with EtOAc (20 mL). The pooled organic layers were washed with brine, dried (MgSO ₄ ) and filtered. The solvent was evaporated in vacuo to give compound 7 (410 mg, 90%). LC / MS (Method _A): t R = 2.46 ^{min,> 95%, m / z} (ESI +) = 379 (MH +).

Example 5 4-Hydroxy-cyclopentane-1,2-dicarboxylic acid 1-[(1-cyclopropanesulfonylaminocarbonyl-2-vinyl-cyclopropyl) -amide] 2- (hex-5-enyl-methyl- Synthesis of (amide) (8)

Crude acid 7 (410 mg, 1.09 mmol) was dissolved in DMF (1.5 mL) and DCM (4.5 mL), followed by the addition of EDAC (417 mg, 2.18 mmol) at room temperature. The mixture was incubated at room temperature with stirring. After 10 minutes, DMAP (133 mg, 1.09 mmol) was added followed by an additional 20 minutes incubation at room temperature. This was followed by the addition of a pre-mixed solution of cyclopropanesulfonic acid amide (527 mg, 4.36 mmol) and DBU (633 mg, 4.36 mmol) in DMF (2 mL) and DCM (2 mL), followed by in a microwave oven. At 100 ° C. for 30 minutes. The resulting red solution was concentrated in vacuo and re-dissolved in EtOAc (20 mL). The organic phase was washed with 1M HCl (aq) (3 × 10 mL) and brine (10 mL), dried (MgSO ₄ ) and filtered. The solvent was evaporated in vacuo to give the crude sulfonamide, which was further purified by chromatography (silica, EtOAc: MeOH, 97.5: 2.5) to give the desired compound 8 (403 mg, 77%). . LC / MS (Method A): t _R = 3.31 min,> 95%, m / z (ESI ⁺ ) = 482 (MH ⁺ )

Example 6-1 : 2,3-dihydroindole-1-carboxylic acid 3- (1-cyclopropane-sulfonylaminocarbonyl-2-vinylcyclopropylcarbamoyl) -4- (hex-5-enylmethyl-carbamoyl) cyclopentyl ester Synthesis of (11)

Compound 8 (19.4 mg, 40 μmol) was dissolved in DCM (1.8 mL) followed by addition of solid NaHCO ₃ (14 mg, 160 μmol) and a stir bar. To this slurry was then added phosgene in toluene (1.93 M, 430 μl, 0.8 mmol) and the mixture was stirred vigorously for 2 hours to give chloroformate 9. LC / MS (Method _G): t R = 2.65 ^{min,> 95%, m / z} (ESI +) = 544 (MH +). The solvent was evaporated in vacuo and the residue was co-evaporated 3 times with DCM to remove residual phosgene. The given chloroformate 9 was then re-dissolved in DCM (1 mL) and 2,3 dihydroindole (68 μmol) was added. The mixture was stirred at ambient temperature for 2 hours after which time LC / MS showed complete conversion. DCM (1 mL) was then added to the mixture and the solution was washed twice with 1M HCl (aq), NaHCO ₃ (aq) and brine. The organic phase was dried (MgSO ₄ ) and filtered. Evaporation of the solvent in vacuo gave a crude material that was further purified by preparative LC / MS to give compound 10: LC / MS (Method H): t _R = 1.58 min,> 95%, m / z (ESI ⁺ ) = 627 (MH ⁺ )

Example 6-2 : 3,4-dihydro-2H-quinoline-1-carboxylic acid 3- (1-cyclopropanesulfonylaminocarbonyl-2-vinylcyclopropylcarbamoyl) -4- (hex-5-enylmethylcarbamoyl) Cyclopentyl ester (11)

The title compound was synthesized from 1,2,3,4-tetrahydroquinoline according to the method described in Example 6-1. LC / MS (Method _H): t R = 1.74 ^{min,> 95%, m / z} (ESI +) = 641 (MH +)

Example 6-3 : 2,3-dihydrobenzo [1,4] oxazine-4-carboxylic acid 3- (1-cyclopropanesulfonylaminocarbonyl-2-vinylcyclopropylcarbamoyl) -4- (hex-5-enyl) Methylcarbamoyl) cyclopentyl ester (12)

The title compound was synthesized from 3,4-dihydro-2H-benzo [1,4] oxazine according to the method described in Example 6-1. LC / MS (Method _H): t R = 1.56 ^{min,> 95%, m / z} (ESI +) = 643 (MH +)

Example 6-4 : 1,3-Dihydroisoindole-2-carboxylic acid 3- (1-cyclopropanesulfonylaminocarbonyl-2-vinylcyclopropylcarbamoyl) -4- (hex-5-enylmethylcarbamoyl) cyclopentyl ester (13)

The title compound was synthesized from 2,3-dihydro-1H-isoindole according to the method described in Example 6-1. LC / MS (Method _H): t R = 1.37 ^{min,> 95%, m / z} (ESI +) = 627 (MH +)

Example 7 : 3,4-Dihydro-1H-isoquinoline-2-carboxylic acid 3- (1-cyclopropanesulfonylaminocarbonyl-2-vinylcyclopropylcarbamoyl) -4- (hex-5-enylmethylcarbamoyl) cyclopentyl ester (16)

p-Nitrophenyl chloroformate (25.9 mg, 0.129 mmol) was dissolved in MeCN (1 mL). To this solution was added solid NaHCO ₃ (15.7 mg, 0.19 mmol) and the suspension was cooled in an ice / water bath. To the cooled solution was then added a solution of 1,2,3,4-tetrahydro-isoquinoline (0.123 mmol) in MeCN (0.5 mL) and the reaction was incubated at ambient temperature for 2 hours. LC / MS analysis showed complete conversion to compound 15. This solution was then added to a mixture of 8 (49.2 mg, 102 μmol) and NaH (60% in oil) (4.5 mg, 112 μmol), followed by heating the reaction to 50 ° C. for 1 hour. The reaction was quenched with NH ₄ Cl (aq) (5 mL) and EtOAc (5 mL) was added. The organic layer was washed with 1M HCl (aq) and brine, dried (MgSO ₄ ) and filtered. Evaporation of the solvent gave an oil that was further purified using preparative LC / MS to give the desired product 16: LC / MS (Method X): t _R = 5.13 min,> 90%, m / z (ESI ⁺ ) = 641 (MH ⁺ )

Example 8-1 : 2,3-dihydroindole-1-carboxylic acid 4-cyclopropanesulfonylaminocarbonyl-13-methyl-2,14-dioxo-3,13-diazatricyclo [13.3.0.0 ^{4, 6} ] octadece-7-en-17-yl ester (17)

Compound 10 (14.6Myu mol), (dried over molecular sieves, _{N 2} - gas treatment _(N 2 _-gassed)) microwave reaction DCE in the vessel of 20mL with a stir bar and dissolved in (10 mL). To this solution was added Hoveyda-Grubb second generation catalyst (2.3 mg, 3.6 μmol) and the reaction vessel was purged with N ₂ (gas) and sealed. 1 reactant
Irradiated for 15 minutes using a set temperature of 50 ° C. The solvent was removed in vacuo and the residue was purified by flash chromatography (silica; DCM, then 10% MeOH in DCM). The product was subsequently purified by preparative LC / MS to give the target compound 17: LC / MS (Method H): t _R = 1.13 min,> 95%, m / z (ESI ⁺ ) = 599 (MH ⁺ )

Example 8-2. 3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-cyclopropanesulfonylaminocarbonyl-13-methyl-2,14-dioxo-3,13-diaza-tricyclo [13.3. 0.0 ^4,6] octadec-7-en-17-yl ester (18)

3,4-Dihydro-1H-isoquinoline-2-carboxylic acid 3- (1-cyclopropanesulfonylaminocarbonyl-2-vinylcyclopropylcarbamoyl) -4- (hex-5) according to the method described in Example 8-1 The title compound was prepared from -enylmethylcarbamoyl) cyclopentyl ester (16). LC / MS (Method A): t _R = 4.51 min,> 95%, m / z (ESI ⁺ ) = 613 (MH ⁺ )

Example 8-3 : 2,3-dihydrobenzo [1,4] oxazine-4-carboxylic acid 4-cyclopropanesulfonylaminocarbonyl-13-methyl-2,14-dioxo-3,13-diazatricyclo [13.3 0.0 ^4,6 ] octadece-7-en-17-yl ester (19)

According to the method described in Example 8-1, 2,3-dihydrobenzo [1,4] oxazine-4-carboxylic acid 3- (1-cyclopropanesulfonylaminocarbonyl-2-vinylcyclopropylcarbamoyl) -4- ( The title compound was prepared from hex-5-enylmethylcarbamoyl) cyclopentyl ester (12): LC / MS (Method H): t _R = 1.11 min,> 95%, m / z (ESI ⁺ ) = 615 ( MH ⁺ )

Example 8-4 : 1,3-dihydro-isoindole-2-carboxylic acid 4-cyclopropanesulfonylaminocarbonyl-13-methyl-2,14-dioxo-3,13-diaza-tricyclo [13.3.0 0.0 ^4,6 ] octadece-7-en-17-yl ester (20)

1,3-Dihydroisoindole-2-carboxylic acid 3- (1-cyclopropanesulfonylaminocarbonyl-2-vinylcyclopropylcarbamoyl) -4- (hex-5-enyl) according to the method described in Example 8-1 The title compound was prepared from (methylcarbamoyl) cyclopentyl ester (13): LC / MS (Method F): t _R = 2.33 min,> 95%, m / z (ESI ⁺ ) = 599 (MH ⁺ )

Example 8-5 : 3,4-dihydro-2H-quinoline-1-carboxylic acid 4-cyclopropanesulfonylaminocarbonyl-13-methyl-2,14-dioxo-3,13-diaza-tricyclo [13.3. 0.0 ^4,6] octadec-7-en-17-yl ester (21):

3,4-Dihydro-2H-quinoline-1-carboxylic acid 3- (1-cyclopropanesulfonylaminocarbonyl-2-vinylcyclopropylcarbamoyl) -4- (hexe-5) according to the method described in Example 8-1 The title compound was prepared from -enylmethylcarbamoyl) cyclopentyl ester (11): LC / MS (Method H): t _R = 1.25 min,> 95%, m / z (ESI ⁺ ) = 613 (MH ⁺ )

Example 9

2- (1-Ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl) -4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (22)
Boc-protected 4-hydroxyproline (4 g, 17.3 mmol), HATU (6.9 g, 18.2 mmol) and 1-amino-2 prepared as described in WO 03/099274 -Vinyl-cyclopropanecarboxylic acid ethyl ester (3.5 g, 18.3 mmol) was dissolved in DMF (60 ml) and cooled to 0 ° C on an ice-bath. Diisopropylethylamine (DIPEA) (6 ml) was added. The ice-bath was removed and the mixture was left overnight at ambient temperature. Dichloromethane (˜80 ml) was then added and the organic phase was washed with aqueous sodium bicarbonate, citric acid, water, brine and dried over sodium sulfate. Purification by flash chromatography (ether → 7% methanol in ether) gave the pure title compound (6.13 g, 96%).

Example 10

2- (1-Ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl) -4- (4-nitro-benzoyloxy) -pyrrolidine-1-carboxylic acid tert-butyl ester (23)
Compound 22 (from Example 9) (11.8 g, 32.0 mmol) and pyridine (27 ml, 305 mmol) were dissolved in DCM (200 ml), cooled to 0 ° C. and 4-nitrobenzoyl chloride (6. 6 g, 35.6 mmol) was added and the solution was stirred at room temperature overnight. The reaction mixture was washed with NaHCO ₃ (aq), aqueous citric acid and brine, dried over MgSO ₄ and evaporated on silica. The crude product was purified by column chromatography on silica (EtOAc / n-heptane: 50/50) to give 11.84 g, 72% of the title compound 5.

Example 11

4-Nitro-benzoic acid 5- (1-ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl) -pyrrolidin-3-yl ester (24)
Compound 23 (11.84 g, 22.9 mmol) was deprotected in TFA (30 ml) dissolved in DCM (100 ml) and then worked up by methods known in the chemical art to give the title compound (9. 37 g, 98%).

Example 12

4-Nitro-benzoic acid 5- (1-ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl) -1- [hept-6-enyl- (4-methoxy-benzyl) -carbamoyl] -pyrrolidin-3-yl ester ( 25)
Compound 24 (4.68 g, 11.2 mmol) was dissolved in THF (100 ml) and NaHCO ₃ (s) (ca. 5 ml) was added followed by phosgene-solution (20% in toluene, 11.6 ml, 22.5 mmol) was added. The reaction mixture was stirred vigorously for 1 hour, then filtered, evaporated and dissolved in DCM (100 ml). NaHCO ₃ and (s) (about 5ml) was added followed by hept-6-enyl - (4-methoxy - benzyl) - was added amine (3.92 g, 16.8 mmol). The reaction mixture was stirred at room temperature overnight, filtered and evaporated on silica. The crude product was purified by column chromatography on silica (EtOAc / n-heptane: 25/75) to give the title compound (6.9 g, 91%).

Example 13

14- (4-Methoxy-benzyl) -18- (4-nitro-benzoyloxy) -2,1
5-Dioxo-3,14,16-triaza-tricyclo [14.3.0.0 ^* 4,6 ^* ] nonadece-7-ene-4-carboxylic acid ethyl ester (26)
Compound 25 (406 mg, 0.6 mmol) was dissolved in DCE (250 ml) and degassed. Hoveyda-Grubbs second generation catalyst (26 mg, 0.042 mmol) was added and the solution was heated to reflux. After 3 hours, the solution was evaporated and used directly in the next step.

Example 14

18-hydroxy-14- (4-methoxy-benzyl) -2,15-dioxo-3,14,16-triaza-tricyclo [14.3.0.0 ^* 4,6 ^* ]-nonadece-7-ene- 4-carboxylic acid ethyl ester (27)
Crude compound 26 (445 mg) was dissolved in THF (20 ml), MeOH (10 ml) and water (10 ml). After cooling to 0 ° C., 1M LiOH (2 ml) was added. Hydrolysis was complete after 1.5 hours, HOAc (1 ml) was added and the solution was evaporated to about 10 ml. Water was added and the mixture was extracted with DCM (2 × 30 ml). The pooled organic phase was washed with NaHCO ₃ (aq), water, brine and dried over MgSO ₄ . The crude product was purified by column chromatography on silica (DCM / MeOH: 100 / 0-80 / 20) to give the title compound (201 mg, 67%).

Example 15

18-Ethoxymethoxy-14- (4-methoxy-benzyl) -2,15-dioxo-3,14,16-triaza-tricyclo [14.3.0.0 ^* 4,6 ^* ]-nonadece-7-ene -4-carboxylic acid ethyl ester (28)
To a stirred solution of alcohol 27 (1.35 g, 2.70 mmol, 75% purity) and N-ethyl-diisopropylamine (1.42 ml, 8.1 mmol) in dichloromethane (15 ml) at 0 ° C. was added. Methyl ethyl ether (0.5 ml, 5.4 mmol) was added. After stirring at room temperature, the reaction mixture was cooled to 0 ° C. and additional N-ethyldiisopropylamine (1 ml, 5.7 mmol) and chloromethyl ethyl ether (0.3 ml, 3.2 mmol) were added, then at room temperature. The mixture was further stirred for 16 hours. The reaction mixture was then applied directly onto a silica gel column and eluted using step gradient elution (ethyl acetate 50-80% in hexane). Concentration of the appropriate fractions gave the title compound as a slightly brown syrup that crystallized on standing (0.8 g, 53%). _LR-MS: Calculated for _{C 30 H 44 N 3 O 7} : 558. Measurement value: 558 [M + H]

Example 16

18-Ethoxymethoxy-14- (4-methoxy-benzyl) -2,15-dioxo-3,14,16-triaza-tricyclo [14.3.0.0 ^* 4,6 ^* ] nonadece-7-ene- 4-carboxylic acid (29)
A solution of ester 28 (0.775 g, 1.39 mmol) in 1: 1: 1 THF-methanol-1M LiOH aqueous solution (36 ml) was stirred at room temperature for 3.5 hours, then TLC (95: 5 and 9 : 1 dichloromethane-methanol) and LC-MS showed complete conversion to carboxylic acid. The reaction mixture was then concentrated to about 1/3 of the volume, then diluted with water (10 ml) and acidified to pH about 4 using 10% aqueous citric acid (60 ml), which formed a precipitate. The mixture was washed with ethyl acetate (3 × 25 ml) and the combined organic layers were washed with brine ( ₂ × 50 ml), then dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was concentrated from toluene (3 × 10 ml) which gave the crude title compound as an off-white foam (0.75 g, quantitative). _LR-MS: Calculated for _{C 28 H 40 N 3 O 7} : 530. Measurement value: 530 [M + H]

Example 17

Compound 30
To a solution of carboxylic acid 29 (about 1.39 mmol) in dichloromethane (10 ml) at room temperature was added N-ethyl-N ′-(3-dimethylaminopropyl) carbodiimide xHCl (0.32 g, 1.67 mmol). And then stirred overnight, after which LC-MS showed complete conversion of the acid to the product. The reaction mixture was then diluted with dichloromethane (10 ml), washed with water (3 × 10 ml), then dried (Na ₂ SO ₄ ), filtered and concentrated to a colorless solid (crude yield: 0.7 g) which Was used immediately in the next step. _LR-MS: Calculated for _{C 28 H 38 N 3 O 6} : 512. Measurement value: 512 [M + H]

Example 18

Cyclopropanesulfonic acid [18-ethoxymethoxy-14- (4-methoxy-benzi
) -2,15-dioxo-3,14,16-triaza-tricyclo [14.3.0.0 ^* 4,6 ^* ] nonadece-7-ene-4-carbonyl] -amide (31)
To a stirred solution of crude oxazolinone 30 (0.328 g, 0.64 mmol) in dichloromethane (4 ml) was added cyclopropylsulfonamide (0.117 g, 0.96 mmol) and 1,8-diazabicyclo [5.4. .0] -undec-7-ene (0.19 ml, 1.3 mmol) was added and then stirred at room temperature overnight. The reaction mixture was monitored by LC-MS, then diluted with dichloromethane (20 ml) and washed successively with 10% aqueous citric acid (3 × 15 ml) and brine (1 × 15 ml), then dried (Na ₂ SO ₄ ) and filtered And concentrated to an off-white foam. Column chromatography of the residue using step gradient elution (ethyl acetate 60-100% in toluene) followed by concentration and drying of the appropriate fractions gave the title compound as a colorless foam (0.27 g, 3 66% through the stage).
NMR data (500 MHz, DMSO-d ₆ ): ¹ H, 0.9-1.6 (m, 14H), 1.80 (m, 1H), 1.90 (m, 1H), 2.0-2 .2 (m, 3H), 2.25 (m, 1H), 2.95 (m, 1H), 3.05 (m, 1H), 3.3-3.4 (m, 2H), 3. 50 (q, 2H), 3.7-3.8 (m, 4H), 3.97 (d, 1H), 4.3-4.4 (m, 2H), 4.55 (d, 1H) , 4.63 (m, 2H), 5.12 (m, 1H), 5.70 (m, 1H), 6.88 (d, 2H), 7.19 (d, 2H), 8.12 ( s, 1H). _{LR-MS: C 31 H 45} N 4 O 8 Calculated for S: 633. Measurement value: 633 [M + H]

Example 19

Cyclopropanesulfonic acid (18-hydroxy-2,15-dioxo-3,14,16-triaza-tricyclo [14.3.0.0 ^* 4,6 ^* ] nonadece-7-ene-4-carbonyl) -amide (32)
A solution of acetal 31 (0.038 g, 0.06 mmol) in 1: 1: 1 THF-methanol-2M aqueous hydrochloric acid (1.5 ml) was stirred at room temperature for 30 minutes, then additional concentrated hydrochloric acid (0. 1 ml) and then stirred at room temperature overnight. The reaction mixture was then neutralized with saturated aqueous sodium bicarbonate and then concentrated onto silica. Flash chromatography of the residue with 9: 1 ethyl acetate-methanol gave a colorless foam (0.020 g, 73%). _{LR-MS: C 20 H 29} N 4 O 6 Calculated for S: 453. Measurement value: 453 [MH]

Example 20-1

1,3-dihydro-isoindole-2-carboxylic acid 4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,14,16-triaza-tricyclo [14.3.0.0 ^* 4,6 ^* ] Nonadece-7-en-18-yl ester (33)
Alcohol 32 (25 mg, 55 umol) was dissolved in dry DCM (2 mL). To this solution was added solid NaHCO ₃ (14 mg, 165 umol) and phosgene (1.9 M in toluene, 868 μL, 1.65 mmol). The mixture was stirred for 48 hours to give the intermediate chloroformate. LC / MS (Method _F): t R = 2.32 ^{min, m / z (ESI +)} = 516 (MH +). The solvent was removed in vacuo and the residue was co-evaporated with DCM to remove residual phosgene. The chloroformate provided is then re-dissolved in dry DCE (2 ml), isoindoline (83 μmol) is added, followed by solid K ₂ CO ₃ (110 μmol) and powdered 4Å molecular sieves (one spatula) added. The mixture was heated to 100 ° C. for 45 minutes, after which time LC / MS analysis showed no residual chloroformate. The reaction was filtered and the filtrate was concentrated in vacuo to give the crude material, which was purified by preparative LC / MS to give the title compound. LC / MS (Method _H): t R = 1.55 ^{min,> 95%, m / z} (ESI +) = 600 (MH +)

Example 20-2

2,3-dihydro-indole-1-carboxylic acid 4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,14,16-triaza-tricyclo [14.3.0.0 ^* 4,6 ^* ] nonadece -7-en-18-yl ester (34)
The title compound was prepared according to the method described in Example 20-1, except that indoline was used instead of isoindoline. LC / MS (Method _H): t R = 1.68 ^{min, 95%, m / z (} ESI +) = 600 (MH +)

Example 20-3

3,4-Dihydro-1H-isoquinoline-2-carboxylic acid 4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,14,16-triaza-tricyclo [14.3.0.0 ^* 4,6 ^* Nonadece-7-en-18-yl ester (35)
The title compound was prepared according to the method described in Example 20-1, except that 1,2,3,4-tetrahydro-isoquinoline was used instead of isoindoline. LC / MS (Method _H): t R = 1.60 ^{min, 95%, m / z (} ESI +) = 614 (MH +)

Example 20-4

3,4-Dihydro-2H-quinoline-1-carboxylic acid 4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,14,16-triaza-tricyclo [14.3.0.0 ^* 4,6 ^* Nonadece-7-en-18-yl ester (36)
The title compound was prepared according to the method described in Example 20-1, except that 1,2,3,4-tetrahydro-quinoline was used instead of isoindoline. LC / MS (Method _H): t R = 1.77 ^{min, 95%, m / z (} ESI +) = 614 (MH +)

Example 20-5

5-methyl-2,3-dihydro-indole-1-carboxylic acid 4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,14,16-triaza-tricyclo [14.3.0.0 ^* 4 6 ^* ] Nonadece-7-en-18-yl ester (37)
The title compound was prepared according to the method described in Example 20-1, except that 5-methyl-2,3-dihydro-1H-indole was used in place of isoindoline. LC / MS (Method _H): t R = 1.91 ^{min, 95%, m / z (} ESI +) = 614 (MH +)

Example 20-6

5-Dimethylsulfamoyl-2,3-dihydro-indole-1-carboxylic acid 4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,14,16-triaza-tricyclo [14.3.0.0 ^* 4,6 ^* ] nonadece-7-en-18-yl ester (38)
The title compound was prepared according to the method described in Example 20-1, except that 2,3-dihydro-1H-indole-5-sulfonic acid dimethylamide was used in place of isoindoline. LC / MS (Method _H): t R = 1.53 ^{min, 95%, m / z (} ESI +) = 707 (MH +)

Example 21: Synthesis of crystalline cyclopentane Synthesis of 3-oxo-2-oxa-bicyclo [2.2.1] heptane-5-carboxylic acid tert-butyl ester (40)

To a stirred solution of 39 (180 mg, 1.15 mmol) in ₂ mL of CH ₂ Cl ₂ was added DMAP (14 mg, 0.115 mmol) and Boc ₂ O (252 mg, 1.44 mmol) in an inert argon atmosphere. Below was added at 0 ° C. The reaction was allowed to warm to room temperature and it was stirred overnight. The reaction mixture was concentrated and the crude product was purified by flash column chromatography (toluene / ethyl acetate gradient 15: 1, 9: 1, 6: 1, 4: 1, 2: 1) which contained the title compound (124 mg, 51%) as white crystals.
¹ H-NMR (300 MHz, CD ₃ OD) δ 1.45 (s, 9H), 1.90 (d, J = 11.0 Hz, 1H), 2.10-2.19 (m, 3H), 2 .76-2.83 (m, 1H), 3.10 (s, 1H), 4.99 (s, 1H); ¹³ C-NMR (75.5 MHz, CD ₃ OD) δ 27.1, 33. 0, 37.7, 40.8, 46.1, 81.1
81.6, 172.0, 177.7.
Alternative method for the preparation of compound 40

Compound 39 (13.9 g, 89 mmol) was dissolved in dichloromethane (200 ml) and then cooled to about −10 ° C. under nitrogen. Isobutylene was then bubbled into the solution until the total volume increased to about 250 mL, which gave a cloudy solution. BF ₃ . Et ₂ O (5.6 ml, 44.5 mmol, 0.5 eq) was added and the reaction mixture was kept at about −10 ° C. under nitrogen. After 10 minutes, a clear solution was obtained. The reaction was monitored by TLC (stained with EtOAc-toluene 3: 2 and hexane-EtOAc 4: 1, acidified with a few drops of acetic acid, basic permanganate solution). At 70 minutes, only a trace amount of compound 39 remained and saturated aqueous NaHCO ₃ (200 ml) was added to the reaction mixture which was then stirred vigorously for 10 minutes. The organic layer was washed with saturated NaHCO ₃ ( ₃ × 200 ml) and brine (1 × 150 ml), then dried over sodium sulfate, filtered and the residue was evaporated to an oily residue. When hexane was added to the residue, the product precipitated. Additional hexane addition and heating to reflux gave a clear solution from which the product crystallized. The crystals were collected by filtration, washed with hexane (room temperature) and then air-dried for 72 hours to give colorless needles (12.45 g, 58.7 mmol, 66%).

Example 22: Activity of compounds of formula (I) Replicon assay Compounds of formula (I) were investigated in cellular assays for activity in inhibiting HCV RNA replication. The assay showed that the compound of formula (I) showed activity against a functional HCV replicon in cell culture. The cell assay is a multi-target screening strategy, as described by Krieger et al. Journal of Virology 75: 2001, 4614-4624, Lohmann et al. Author, Science vol. 285: 1999, 110-113, based on the bicistronic expression construct. In essence, the method was as follows.

The assay used the stably transfected cell line Huh-7 luc / neo (hereinafter referred to as Huh-Luc). This cell line comprises a wild type NS3-NS5B region of type 1b HCV translated from an internal ribosome entry site (IRES) from encephalomyocarditis virus (EMCV), to which a reporter moiety ( FfL-luciferase) and RNA encoding a bicistronic expression construct preceded by a selectable marker moiety (neo ^R , neomycin phosphotransferase). The construct is bounded by 5 'and 3' NTRs (non-translated regions) from type 1b HCV. Continued culture of replicon cells in the presence of G418 (neo ^R ) depends on HCV RNA replication. Stably transfected replicon cells that replicate autonomously and to high levels and express HCV RNA encoding luciferase, among others, were used for screening antiviral compounds.

Replicon cells were plated in 384 well plates in the presence of test and standard compounds added at various concentrations. After 3 days of incubation, HCV replication was measured by assay for luciferase activity (using standard luciferase assay substrates and reagents and a Perkin Elmer ViewLux ^Tm ultraHTS microplate imager). Replicon cells in standard culture have high luciferase expression in the absence of inhibitor. The inhibitory activity of the compound on luciferase activity was monitored on Huh-Luc cells, allowing a dose-response curve for each test compound. An EC50 value is then calculated, which is the amount of compound required to reduce the level of luciferase activity detected, or more specifically, the ability of the genetically linked HCV replicon RNA to replicate by 50%. Show.

Inhibition assay The purpose of this in vitro assay was to measure the inhibition of the HCV NS3 / 4A protease complex by the compounds of the present invention. This assay provides an indication of how effective the compounds of the invention are in inhibiting HCV NS3 / 4A proteolytic activity.

Inhibition of full-length hepatitis C NS3 protease enzyme is essentially the same as Poliakov, 2002.
Measured as described in Prot Expression & Purification 25 363 371. In short, hydrolysis of the depsipeptide substrate, Ac-DED (Edans) EEAbuψ [COO] ASK (Dabcyl) -NH ₂ (AnaSpec, San Jose, USA) , Uppsala University, Sweden). [Landro, 1997 #Biochem 36 9340-9348]. Enzyme (1 nM) was added for 10 minutes at 30 ° C. in 50 mM HEPES, pH 7.5, 10 mM DTT, 40% glycerol, 0.1% n-octyl-D-glucoside with 25 μM NS4A cofactor and inhibitor. Incubation was then initiated by addition of 0.5 μM substrate. Inhibitors were dissolved in DMSO, sonicated for 30 seconds and vortexed. The solution was stored at −20 ° C. between measurements.

  The final concentration of DMSO in the assay sample was adjusted to 3.3%. The rate of hydrolysis was corrected for internal filter effect according to published methods. [Liu, 1999 Analytical Biochemistry 267 331-335]. Ki values were estimated by non-linear regression analysis (GraFit, Erithacus Software, Stains, MX, UK) using a model for competitive inhibition and a fixed value for Km (0.15 μM). For all measurements, a minimum of 2 repetitions were performed.

  Table 1 below lists compounds that were prepared according to any one of the above examples. The activity of the compounds investigated is also listed in Table 1.

Claims (12)

formula

[Wherein each dotted line (indicated by -----) indicates an optional double bond;
X is N, CH, and if X contains a double bond, it is C;
R ¹ is —OR ⁶ , —NH—SO ₂ R ⁷ ;
R ² is hydrogen, and when X is C or CH, R ² can also be C _1-6 alkyl;
R ³ is hydrogen, C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl or C _3-7 cycloalkyl;
n is 3, 4, 5 or 6;
R ⁴ and R ⁵ together with the nitrogen atom to which they are attached

Forming a bicyclic ring system selected from: wherein the ring system is optionally halo, hydroxy, oxo, nitro, cyano, carboxyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkoxy C Substituted with 1, 2 or 3 substituents independently selected from _1-6 alkyl, C _1-6 alkylcarbonyl, C _1-6 alkoxycarbonyl, amino, azide, mercapto, polyhaloC _1-6 alkyl Can be;
R ⁶ is hydrogen; aryl; Het; C _3-7 cycloalkyl optionally substituted with C _1-6 alkyl; or optionally substituted with C _3-7 cycloalkyl, aryl or Het C _1-6 alkyl which can be
R ⁷ is aryl; Het; C _3-7 cycloalkyl optionally substituted with C _1-6 alkyl; or optionally substituted with C _3-7 cycloalkyl, aryl or Het C _1-6 alkyl;
Aryl as a group or part of a group is phenyl or naphthyl, each of which is optionally halo, hydroxy, nitro, cyano, carboxyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkoxyC _1-6 alkyl, C _1-6 alkylcarbonyl, amino, mono- or diC _1-6 alkylamino, azide, mercapto, polyhalo C _1-
1 , selected from ₆ alkyl, polyhalo C _1-6 alkoxy, C _3-7 cycloalkyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-C _1-6 alkyl-piperazinyl, 4-C _1-6 alkylcarbonyl-piperazinyl and morpholinyl; Can be substituted with 2 or 3 substituents; where the morpholinyl and piperidinyl groups can optionally be substituted with 1 or 2 C _1-6 alkyl groups;
Het as a group or part of a group is a 5 or 6 membered saturated, partially unsaturated or fully unsaturated containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, respectively A heterocyclic ring and optionally halo, hydroxy, nitro, cyano, carboxyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkylcarbonyl, respectively , Amino, mono- or diC _1-6 alkylamino, azide, mercapto, polyhaloC _1-6 alkyl, polyhaloC _1-6 alkoxy, C _3-7 cycloalkyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-C _{1- 6} alkyl - piperazinyl, _{4-C 1-6} alkylcarbonyl - independently from the group consisting of piperazinyl and morpholinyl That Te is substituted with 1, 2 or 3 substituents selected can be; wherein morpholinyl and piperidinyl groups may be substituted with one or two C _1-6 alkyl groups optionally]
, N-oxides, salts or stereoisomers thereof. The compound is of formula (Ic), (Id) or (Ie):

A compound according to claim 1 having: R ⁴ and R ⁵ together with the nitrogen atom to which they are attached

Forming a bicyclic ring system selected from wherein the phenyl of the bicyclic ring system is optionally halo, hydroxy, cyano, carboxyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkoxy - carbonyl, amino and polyhalo C _1-6 compound according to any one of claims 1-2 which may be substituted with 1 or 2 substituents independently selected from alkyl. R ⁴ and R ⁵ together with the nitrogen atom to which they are attached

In which the pyrrolidine, piperidine or morpholine ring of the bicyclic ring system is optionally C _1-6 alkyl, C _1-6 alkoxy and C _1-6 alkoxy C _1- the compound according to any one of claims 1-2 which may be substituted with 1 or 2 substituents independently selected from _alkyl. (A) R ¹ is —OR ⁶ where R ⁶ is C _1-6 alkyl or hydrogen; or (b) R ¹ is —NHS (═O) ₂ R ⁷ where R 1 ^{7. A} compound according to any one of claims 1 to 4, wherein ⁷ is methyl, cyclopropyl or phenyl.   6. A compound according to any one of claims 1 to 5 other than N-oxide or salt. (A) a compound as defined in any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof; and (b) ritonavir; or a pharmaceutically acceptable salt thereof. A combination of   A pharmaceutical composition comprising an anti-virally effective amount of a compound according to any one of claims 1 to 6 or a combination according to claim 7 as carrier and active ingredient.   A compound according to any of claims 1 to 6 or a combination according to claim 7 for use as a medicament.   Use of a compound according to any of claims 1-6 or a combination according to claim 7 for the manufacture of a medicament for the inhibition of HCV replication.   A method of inhibiting HCV replication in a warm-blooded animal comprising administering an effective amount of a compound according to any of claims 1-6 or an effective amount of each component of a combination according to claim 7. (A) The following reaction scheme:

Is a compound of formula (Ii) by forming a double bond between C ₇ and C ₈ and simultaneously cyclizing to a macrocycle, especially via an olefin metathesis reaction Preparing a compound of formula (I) wherein the bond between C ₇ and C ₈ is a double bond;
Here, in the reaction schemes described above and below, R ⁸ is a group.

Indicates;
(B) Reduction of the C7-C8 double bond in the compound of formula (Ij) to the compound of formula (Ii) results in a bond between C7 and C8 in the macrocycle Compounds of formula (I), ie formula (Ij):

To the compound of
(C) G is based:

As outlined in the scheme below, R ¹ represented by formula (Ik-1) is —NHSO ₂ by forming an amide bond between intermediate (2a) and sulfonylamine (2b). A compound of formula (I) in which R ¹ represents —OR ⁶ is prepared by preparing a compound of formula (I) representing R ⁷ or by forming an ester bond between intermediate (2a) and alcohol (2c). Producing a compound, ie compound (Ik-2);

(D) preparing a compound of formula (I) wherein R ³ represented by (I-1) is hydrogen from the corresponding nitrogen-protected intermediate (3a):

Where PG represents a nitrogen protecting group,
(E) The following reaction scheme:

Reacting intermediate (4a) with amine (4b) in the presence of a carbamate-forming reagent, as outlined in
(F) converting the compounds of formula (I) to each other by a functional group conversion reaction; or (g) preparing the salt form by reacting the free form of the compound of formula (I) with an acid or base. The manufacturing method of the compound in any one of Claims 1-6 which comprise these.